Evaluating the effect of sorafenib on Gd-EOB-DTPA-mediated contrast enhancement: An experimental study using DCE-MRI

Evaluating the effect of sorafenib on Gd-EOB-DTPA-mediated contrast enhancement: An experimental study using DCE-MRI | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluating the effect of sorafenib on Gd-EOB-DTPA-mediated contrast enhancement: An experimental study using DCE-MRI Yeon Ji Chae, Do-Wan Lee, Chul-Woong Woo, Yu Sub Sung, Jung-Hyun Choi, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7747491/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Purpose Despite the potential impact of sorafenib on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-mediated contrast enhancements, attempts to assess these effects are rare. This study aimed to investigate the interaction between Sorafenib and Gd-EOB-DTPA by quantifying the T1 and T2 relaxation times and the relative enhancement rates (RERs) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the liver. Procedures: The effects on contrast enhancement were assessed using MRI with Chang liver cells and SD rats. MR phantom images were obtained after treating cells with varying dosages of Gd-EOB-DTPA (5, 10 mM) and sorafenib (10, 30 µM) to evaluate MR relaxivities. For the animal study, DCE-MRI was performed following intravenous administration of 25 µmol/kg Gd-EOB-DTPA and two different doses of sorafenib (10, 30 mg/kg). RER was analyzed to evaluate sorafenib's effects on Gd-EOB-DTPA uptake in the liver. Results Phantom experiments demonstrated alterations in T1 and T2 values, with a tendency towards shortening disrupted by the addition of Sorafenib to Gd-EOB-DTPA-treated Chang liver cells. The RERs of DCE-MRI in the liver exhibited a dose-dependent decrease following sorafenib administration, with recovery observed after 4 h. Conclusions Our results provide quantitative information on sorafenib-mediated interference with Gd-EOB-DTPA-induced contrast enhancement and offer experimental evidence suggesting the possibility of drug-drug interactions between sorafenib and Gd-EOB-DTPA. Although further research is needed to fully elucidate the impact of these interactions, caution is warranted when using these two agents concurrently for liver MRI. Sorafenib Gd-EOB-DTPA Cellular Uptake Inhibition Drug Interactions DCE-MRI Figures Figure 1 Figure 2 Figure 3 Introduction Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is utilized for anatomical magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI (DCE-MRI) of the liver [ 1 , 2 , 3 , 4 , 5 ]. Its unique properties, particularly its high affinity for the Organic Anion Transporting Protein (OATP) family specifically OATP1B1 and OATP1B3, which are prominently expressed in the liver enable Gd-EOB-DTPA-enhanced MRI to provide detailed anatomical images of the liver and its vasculature [ 6 , 7 , 8 , 9 ]. Sorafenib is a multi-kinase inhibitor that targets several tyrosine kinase pathways, including Raf, VEGFR, and PDGFR. [ 10 , 11 ] Given that these pathways are intricately involved in tumor cell proliferation and angiogenesis, sorafenib has garnered significant attention as an effective therapeutic agent for various cancers [ 12 , 13 , 14 ] However, multiple studies have explored the interaction between sorafenib and OATPs, revealing that sorafenib can modify the transport activities of OATP1B1 and OATP1B3 [ 15 , 16 , 17 ]. Therefore, sorafenib affects OATP transport activity in hepatocytes, leading to alterations in the influx and efflux of Gd-EOB-DTPA, which may result in changes to the contrast observed in liver MRI when sorafenib is administered to patients with hepatocellular carcinoma. Notably, numerous studies have concurrently utilized sorafenib and Gd-EOB-DTPA to test their respective hypotheses [ 18 , 19 , 20 ]. However, most of these studies focused on the individual functionalities of sorafenib and Gd-EOB-DTPA without quantifying the extent to which sorafenib affects Gd-EOB-DTPA over time and dosage. Furthermore, although previous investigations regarding the effects of various tyrosine kinase inhibitors on Gd-EOB-DTPA uptake indicated negligible effects, sorafenib was not included in those experiments [ 21 , 22 ]. Chang liver cells, which were used as an in vitro model in this study, have been widely reported to originate from HeLa cells rather than hepatocytes. Despite this origin, the use of Chang liver cells was deemed suitable for this study, as the expression of OATP transporters was confirmed by qPCR and immunofluorescence analysis [ 23 , 24 ]. Considering that the primary objective of this study was to evaluate OATP-mediated drug-drug interactions rather than hepatocyte-specific metabolic functions, the cell origin is unlikely to have influenced the validity of the experimental outcomes. Therefore, the purpose of this study was to assess and quantify the effect of sorafenib on Gd-EOB-DTPA-induced contrast enhancements. Materials and Methods MR phantom preparations Serially diluted Gd-EOB-DTPA (Primovist®, BayerPharma, Berlin, Germany) solutions were prepared as reference phantoms in 0.2-mL tubes at concentrations of 0, 5, 32.5, and 125 µM. Chang liver cells were cultured in Dulbecco's Modified Eagle Medium (Gibco, Grand Island, NY, USA) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin solution. The cells were incubated at 37°C in a humidified atmosphere containing 5% CO 2 . For the cell phantoms, the cells were treated with Gd-EOB-DTPA for 6 h, sorafenib (SML2633, Sigma-Aldrich, St. Louis, MO, USA), or a combination of both agents at the following concentrations: Gd-EOB-DTPA at 5 mM or 10 mM, and sorafenib at 10 mM or 30 mM. The cells were subsequently washed twice using phosphate buffered saline, and 3 × 10 6 cells were harvested and transferred to 0.2-mL tubes. After centrifugation at 500 g for 10 min, the supernatants were carefully removed, and the tubes were sealed with 1% agarose gel. In vitro MRI and relaxivity measurements For the measurements of the MR relaxivities (r1 and r2), T1 and T2 mapping images were acquired using the following MR parameters: (1) T1 mapping with eight inversion times (TI) = [20, 100, 200, 400, 800, 1000, 2000, 4000] ms, repetition time (TR) = 5000 ms, echo time (TE) = 7.10 ms, average = 1, slice thickness = 1.0 mm, matrix size = 96 × 96, and field of view (FOV) = 70 × 60 mm 2 ; (2) T2 mapping with 15 TEs = [10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150] ms, TR = 3000 ms, average = 1, slice thickness = 1.0 mm, matrix size = 96 × 96, and FOV = 70 × 60 mm 2 . T1 and T2 values were analyzed by selecting regions of interest in different tubes. In vitro MRI was conducted using a 9.4-T magnet (Agilent, Inc., Santa Clara, CA, USA) and MR relaxivities were calculated using Asan J software, an analytic software derived from ImageJ (NIH, Bethesda, MA, USA). Animals Sixteen male Sprague–Dawley rats (n = 16; 8 weeks old) were obtained from Orient Animal Laboratory (Seoul, South Korea) and randomly divided into experimental groups, each containing four animals. All rats were maintained at a controlled room temperature of 22 ± 2°C, humidity of 55 ± 5%, and a 12:12-hour light-dark cycle. All procedures received approval from the Institutional Animal Care and Use Committee of Asan Medical Center (IACUC No. 2024-10-024), and experiments were conducted according to relevant guidelines for ethical animal experimentation. Sorafenib was dissolved in a mixture of 1% dimethyl sulfoxide and 40% sulfobutyl ether β-Cyclodextrin (Thermo Fisher Scientific, Sunnyvale, CA, USA) in normal saline, and the solution was filtered through a 0.45-µm membrane filter prior to administration. Sorafenib was administered intravenously at doses of 10 or 30 mg/kg just before MRI acquisition. In vivo MRI and analyses Animal MRIs were conducted using a 9.4-T magnet (Agilent, Inc., Santa Clara, CA, USA) equipped with a 64-mm transmit/receive volume coil. All animals were maintained under respiratory anesthesia with a 1.5–2% isoflurane/air mixture, and their body temperature was regulated at 37.5 ± 0.5°C using an air heater system. The respiratory rate was continuously monitored to allow for adjustments in anesthetic concentration. T1-weighted DCE-MRI scans were acquired following the intravenous administration of 25 µmol/kg Gd-EOB-DTPA after 120 s. The specific imaging parameters were as follows: TR/TE = 70/2.34 ms, flip angle = 35°, average = 1, matrix size = 96 × 96, FOV = 50 × 50 mm², total scan time = 44 min 48 s, and total number of images = 400. Animal MRI data were analyzed using Asan J software, which integrates ImageJ and MATLAB (The MathWorks, Natick, MA, USA). Regions of interest were randomly placed within the liver, avoiding visible blood vessels, and subsequent measurements were taken. The RER was calculated using the equation RER = [{SI(t) − SI(0)} / SI(0)] × 100 (%), where SI(t) represents the signal intensity of the liver at time t, and SI(0) denotes the average signal intensity prior to Gd-EOB-DTPA injection. Various quantitative parameters were derived from the signal intensity curve, including time to maximum (Tmax), area under the curve from 0 to 6 min (AUC Tmax ), wash-in rate slope (WiR), and wash-out rate slope (WoR), as illustrated in Fig. 1 . Statistical analysis Statistical analyses were performed using IBM SPSS for Windows version 21.0 (IBM Corp., Armonk, NY, USA). Various MR values were compared using a one-way analysis of variance with Tukey’s post-hoc test. A p-value of less than 0.05 was considered statistically significant. Results T1 and T2 relaxation times of Gd-EOB-DTPA and sorafenib-treated cells Phantom images were first acquired to determine the reference T1 and T2 relaxation times of various concentrations of Gd-EOB-DTPA (0, 5, 32.5, and 125 µM). As the concentration of Gd-EOB-DTPA increased, T1 and T2 values decreased. The T1 and T2 relaxation times were as follows: 0 µM, 2887.6 ± 4.2 ms; 5 µM, 2437.7 ± 24.4 ms; 32.5 µM, 1598.0 ± 10.9 ms; and 125 µM, 703.6 ± 16.6 ms; vs. 0 µM, 1441.2 ± 35.1 ms; 5 µM, 1393.0 ± 57.6 ms; 32.5 µM, 1061.8 ± 26.4 ms; and 125 µM, 501.4 ± 9.7 ms; respectively; Fig. 2 A–D). Subsequently, T1 and T2 relaxation times were measured using Chang liver cell phantoms to evaluate the impact of sorafenib on the uptake of Gd-EOB-DTPA in these cells. Notably, T1 and T2 values decreased following treatment with Gd-EOB-DTPA (5 mM and 10 mM) compared to untreated cells. However, when the cells were treated with both Gd-EOB-DTPA (10 mM) and sorafenib (10 µM or 30 µM), T1 and T2 values increased, suggesting that sorafenib influenced the amount of Gd-EOB-DTPA present in the cells. The degree of interference in T1 and T2 shortening intensified with increasing concentrations of sorafenib. The T1 and T2 values for each experimental condition were as follows: Untreated Group (T1: 1525.7 ± 83.9 ms, T2: 70.9 ± 2.0 ms), Gd-EOB-DTPA 5 mM Group (T1: 916.7 ± 421.1 ms, T2: 42.7 ± 8.8 ms), Gd-EOB-DTPA 10 mM Group (T1: 659.8 ± 15.1 ms, T2: 31.2 ± 6.0 ms), Gd-EOB-DTPA 10 mM + Sfb 10 µM Group (T1: 787.0 ± 897.7 ms, T2: 52.3 ± 51.6 ms), and Gd-EOB-DTPA 10 mM + Sfb 30 µM Group (T1: 1008.1 ± 98.6 ms, T2: 83.0 ± 4.6 ms; Fig. 2 B–D). Evaluating the effects of sorafenib on contrast enhancement in rats We investigated the effects of sorafenib on contrast enhancement in SD rats using varying concentrations (vehicle, 10 mg/kg, 30 mg/kg) and time points (30 min and 4 h post-administration; Fig. 3 A-B). DCE-MRI time-intensity curves were analyzed to assess both concentration- and time-dependent changes (Fig. 3 C–E). The time to maximum signal intensity (Tmax) exhibited a dose-dependent increase in the sorafenib-treated groups compared to the vehicle group, with a partial recovery observed in the 4-h group (Tmax: 16.20 ± 1.80 for vehicle, 12.11 ± 0.22 for Sfb 10 mg/kg at 30 min, 8.52 ± 3.93 for Sfb 30 mg/kg at 30 min, and 12.72 ± 2.62 for Sfb 30 mg/kg at 4 h; Fig. 3 F). The area under the curve until Tmax (AUC Tmax ) demonstrated a concentration-dependent decrease, with signs of recovery at 4 h post-administration (AUC Tmax : 16.20 ± 1.80 for vehicle, 12.11 ± 0.22 for Sfb 10 mg/kg, 8.52 ± 3.93 for Sfb 30 mg/kg, and 12.72 ± 2.62 for Sfb 30 mg/kg at 4 h; Fig. 3 G). The WiR exhibited a similar pattern, revealing reduced values in sorafenib-treated groups and partial recovery at 4 h (WiR: 1.88 ± 0.32 for vehicle, 0.75 ± 0.10 for Sfb 10 mg/kg, 0.49 ± 0.34 for Sfb 30 mg/kg, and 0.91 ± 0.41 for Sfb 30 mg/kg at 4 h; Fig. 3 H). Conversely, the WoR increased in sorafenib-treated groups, indicating slower contrast clearance, with partial normalization observed at 4 h (WoR: -0.12 ± 0.02 for vehicle, -0.06 ± 0.01 for Sfb 10 mg/kg, -0.05 ± 0.05 for Sfb 30 mg/kg, and − 0.08 ± 0.02 for Sfb 30 mg/kg at 4 h; Fig. 3 I). Collectively, these findings demonstrate the dose- and time-dependent effects of sorafenib on contrast enhancement parameters in vivo. Discussion Our study aimed to investigate the effects of sorafenib treatment on Gd-EOB-DTPA-induced contrast enhancements at both cellular and animal levels. Specifically, we utilized MRI and DCE-MRI to obtain quantified values that represent the impact of sorafenib on Gd-EOB-DTPA-induced contrast enhancements. Alterations in T1 and T2 values from the cell phantom experiment indicate potential interference with Gd-EOB-DTPA uptake when exposed to sorafenib. These results are consistent with previous studies indicating that sorafenib interacts with OATPs, particularly OATP1B1, and inhibits their function [ 15 , 16 , 17 ]. Furthermore, quantitative data from various DCE-MRI parameters, including RER, Tmax, AUC Tmax , WiR, and WoR, support the notion of sorafenib-mediated interference with cellular uptake of the contrast agent. Notably, we observed a time-dependent recovery in RER, as evidenced by the comparative analysis of 30-min and 4-h DCE-MRI scans; however, the dose-dependent analysis indicated a decrease at the 30-min mark. Therefore, the effects of sorafenib on Gd-EOB-DTPA uptake may be reversible over time. There were several limitations to this study. First, we utilized Chang liver cells, which are derived from HeLa cells rather than hepatocytes. However, these cells were selected because previous research has demonstrated their expression of OATP transporters (Supplementary Fig. 1) [ 23 , 24 ]. Given that the primary aim was to investigate transporter-mediated drug-drug interactions rather than functions specific to hepatocytes, employing these cells was deemed suitable for our experiment. Additional studies with primary hepatocytes could provide further validation of our findings. However, the use of primary hepatocytes was not feasible in this study due to the large number of cells required for cell phantom preparation. Second, while sorafenib is typically administered orally in clinical practice, our study utilized intravenous administration. This difference in the route of administration may influence the drug’s pharmacokinetics and, consequently, its effects on Gd-EOB-DTPA uptake. Third, in clinical settings, the recommended daily oral dose of sorafenib for adult patients is 800 mg (400 mg twice daily) [ 25 , 26 ]. Assuming an average adult weight of 70 kg, this translates to approximately 11.4 mg/kg per day. In contrast, our study employed intravenous doses of 10 and 30 mg/kg. Therefore, the doses of sorafenib administered intravenously in our experimental setting were significantly higher than those typically used in clinical practice, even when accounting for differences in bioavailability between oral and intravenous routes. This higher dosage was selected to ensure observable effects in our experimental model and to account for potential differences in drug metabolism between humans and animal models. Consequently, the elevated doses used in our experiments could lead to more substantial effects on Gd-EOB-DTPA uptake compared to standard clinical dosing. Therefore, while our results provide valuable insights to the potential interactions between sorafenib and Gd-EOB-DTPA, the magnitude of these effects in clinical practice may differ due to the lower doses routinely administered to patients. Conclusions Our study presents quantified experimental evidence from both in vitro and in vivo studies, demonstrating that sorafenib interferes with the cellular uptake of Gd-EOB-DTPA. These findings underscore the necessity of considering drug-drug interactions in liver MRI scans, particularly in patients undergoing targeted kinase inhibitor therapy. Further research is needed to elucidate the clinical implications of these interactions. Declarations Author Contributions: Conceptualization: YC, DCW. Data curation: ET, CHH, JKR, IJB, CGP. Formal analysis: CYJ. Investigation: CYJ. Methodology: DWL, CWW, YSS. Project administration: YC. Resources: ET, YC, DCW. Software: DWL, CWW, YSS. Supervision: DCW. Validation: JHC, CHH, JKR, IJB, CGP, KWK, JKK. Visualization: CYJ, HH. Writing—original draft: CYJ, YC, DCW. Writing—review and editing: DWL, CWW, YSS, JHC, ET, CHH, JKR, IJB, CGP, HH, KWK, JKK, YC, DCW. All authors read and approved the final manuscript. Funding : This research was supported by the National Research Foundation of Korea (NRF) (Grant No.2022R1Z1A1A01066589 and 2022R1C1C2008801). Conflicts of Interest: The authors declare that they have no competing interests. Ethics approval: The study was approved by the Institutional Animal Care and Use Committee of Asan Medical Center (IACUC No. 2024-10-024) References Liu HF, Wang Q, Du YN et al (2020) Dynamic contrast-enhanced MRI with Gd-EOB-DTPA for the quantitative assessment of early-stage liver fibrosis induced by carbon tetrachloride in rabbits. Magn Reson Imaging 70:57–63 Saito K, Ledsam J, Sourbron S et al (2013) Assessing liver function using dynamic Gd-EOB-DTPA-enhanced MRI with a standard 5-phase imaging protocol. J Magn Reson Imaging 37(5):1109–1114 Chen BB, Hsu CY, Yu CW et al (2012) Dynamic contrast-enhanced magnetic resonance imaging with Gd-EOB-DTPA for the evaluation of liver fibrosis in chronic hepatitis patients. Eur Radiol 22(1):171–180 Murase K, Kashiwagi N, Tomiyama N (2022) Quantitative evaluation of simultaneous spatial and temporal regularization in dynamic contrast-enhanced MRI of the liver using Gd-EOB-DTPA. Magn Reson Imaging 88:25–37 Jia J, Puls D, Oswald S et al (2014) Characterization of the intestinal and hepatic uptake/efflux transport of the magnetic resonance imaging contrast agent gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid. Invest Radiol 49(2):78–86 Leonhardt M, Keiser M, Oswald S et al (2010) Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos 38(7):1024–1028 Haimerl M, Verloh N, Zeman F et al (2017) Gd-EOB-DTPA-enhanced MRI for evaluation of liver function: Comparison between signal-intensity-based indices and T1 relaxometry. Sci Rep 7(1):43347 Nassif A, Jia J, Keiser M et al (2012) Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging. Radiology 264(3):741–750 Laitinen A, Niemi M (2011) Frequencies of single-nucleotide polymorphisms of SLCO1A2, SLCO1B3 and SLCO2B1 genes in a Finnish population. Basic Clin Pharmacol Toxicol 108(1):9–13 Tang WW, Chen ZY, Zhang WL et al (2020) The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Therapy 5(1):87 Wilhelm S, Carter C, Lynch M et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835–844 Feng GL, Luo Y, Zhang Q, Zeng F, Xu J, Zhu JQ (2020) Sorafenib and radioiodine-refractory differentiated thyroid cancer (RR-DTC): a systematic review and meta-analysis. Endocrine 68(1):56–63 Bahman A, Abaza MS, Khoushaish S, Al-Attiyah RJ (2023) Therapeutic efficacy of sorafenib and plant-derived phytochemicals in human colorectal cancer cells. BMC Complement Med Ther 23(1):210 Rebaz MA, Sami SO, Fahmi HK et al (2024) Efficacy of Sorafenib in the Management of Non-Small Cell Lung Cancer: A Systematic Review. Barw Med J 2(2):31–38 Hu S, Mathijssen RH, de Bruijn P, Baker SD, Sparreboom A (2014) Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations. Br J Cancer 110(4):894–898 Wen J, Zhao M (2021) OATP1B1 Plays an Important Role in the Transport and Treatment Efficacy of Sorafenib in Hepatocellular Carcinoma. Dis Markers 2021:9711179 Hayden ER, Chen M, Pasquariello KZ et al (2021) Regulation of OATP1B1 Function by Tyrosine Kinase-mediated Phosphorylation. Clin Cancer Res 27(15):4301–4310 Saito K, Ledsam J, Sugimoto K, Sourbron S, Araki Y, Tokuuye K (2018) DCE-MRI for Early Prediction of Response in Hepatocellular Carcinoma after TACE and Sorafenib Therapy: A Pilot Study. J Belg Soc Radiol 102(1):40 Dong Z, Huang K, Liao B et al (2019) Prediction of sorafenib treatment-related gene expression for hepatocellular carcinoma: preoperative MRI and histopathological correlation. Eur Radiol 29:2272–2282 Öcal O, Rössler D, Gasbarrini A et al (2022) Gadoxetic acid uptake as a molecular imaging biomarker for sorafenib resistance in patients with hepatocellular carcinoma: a post hoc analysis of the SORAMIC trial. J Cancer Res Clin Oncol 148(9):2487–2496 Huppertz A, Breuer J, Fels LM et al (2011) Evaluation of Possible Drug-Drug Interaction Between Gadoxetic Acid and Erythromycin as an Inhibitor of Organic Anion Transporting Peptides (OATP). J Magn Reson Imaging 33(2):409–416 Nakamura Y, Hirokawa Y, Kitamura S et al (2013) Effect of lapatinib on hepatic parenchymal enhancement on gadoxetate disodium (EOB)-enhanced MRI scans of the rat liver. Japanese J Radiol 31(6):386–392 Peng JF, Liu L, Guo CX et al (2015) Role of miR-511 in the Regulation of OATP1B1 Expression by Free Fatty Acid. Biomol Ther (Seoul) 23(5):400–406 Lu CC, Chen WK, Chiang JH et al (2018) cDNA Microarray Analysis and Influx Transporter OATP1B1 in Liver Cells After Exposure to Gadoxetate Disodium, a Gadolinium-based Contrast Agent in MRI Liver Imaging. In Vivo 32(3):677 – 84 Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in Advanced Hepatocellular Carcinoma (vol 359, pg 378, 2008). New England Journal of Medicine 359(4):2508–2508 Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134 Supplementary Files Supplementary.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Minor revisions 05 Mar, 2026 Reviewers agreed at journal 23 Oct, 2025 Reviewers invited by journal 23 Oct, 2025 Editor assigned by journal 20 Oct, 2025 First submitted to journal 17 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7747491","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":533826833,"identity":"9ab8dcba-4310-48f1-b503-379f1960d586","order_by":0,"name":"Yeon Ji Chae","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYHCCBAYGAxseNvYGmABzA2MDTtUwLQVpMvw8B2ACjAS1AMGHwzaSMxKI1MI/I+GZNI8BM4/BzcdPN/xgqJPjl0hsYJy5B7cWiRsJaUAtbDwGt9PMbvYwHDaWnAHUsuEZbi0GEglpt3MMeIBaEsxuMzAcSNxwA6jlwQGCWiSADjv+Dailrp5YLQY8kjN4QLYwJxiAtGzAo0XizIP0338MEnj4eXLKbvYYHDac2fOw4eAMPFr423OSDWf8+W/Pxn58240fFXXy/OzJBx/24NHCIJCTgOxOCIVPA9Ca4/jlR8EoGAWjYBQwAAB/mlcPzXrVKQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8609-7082","institution":"University of Ulsan College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Yeon","middleName":"Ji","lastName":"Chae","suffix":""},{"id":533826834,"identity":"a6b4dc54-0129-4ac9-a540-1eb9e4cf99bc","order_by":1,"name":"Do-Wan Lee","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Do-Wan","middleName":"","lastName":"Lee","suffix":""},{"id":533826835,"identity":"7e73f6a9-afab-4a7d-be3b-892734e33a03","order_by":2,"name":"Chul-Woong Woo","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Chul-Woong","middleName":"","lastName":"Woo","suffix":""},{"id":533826836,"identity":"e52ecaa9-df7b-414a-95d7-c3d4a9975728","order_by":3,"name":"Yu Sub Sung","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"Sub","lastName":"Sung","suffix":""},{"id":533826837,"identity":"30092041-54b3-4fb0-a8be-f3f0e4d910a6","order_by":4,"name":"Jung-Hyun Choi","email":"","orcid":"","institution":"Chungbuk National University","correspondingAuthor":false,"prefix":"","firstName":"Jung-Hyun","middleName":"","lastName":"Choi","suffix":""},{"id":533826838,"identity":"ff4a9378-cdcb-4bdd-b924-2e1b584d4bb1","order_by":5,"name":"Eunyoung Tak","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Eunyoung","middleName":"","lastName":"Tak","suffix":""},{"id":533826839,"identity":"12a8a194-9bc7-4ba1-9370-1e7ea28dfdf8","order_by":6,"name":"Chang Hoon Ha","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Chang","middleName":"Hoon","lastName":"Ha","suffix":""},{"id":533826840,"identity":"e9b3cebf-0cc0-4674-9fa9-95087c67aabc","order_by":7,"name":"Jin Kyung Roh","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"Kyung","lastName":"Roh","suffix":""},{"id":533826841,"identity":"a102075b-5a18-4cee-a472-b8b159012cf4","order_by":8,"name":"In-jeong Baek","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"In-jeong","middleName":"","lastName":"Baek","suffix":""},{"id":533826842,"identity":"a236cf89-42ad-46af-86aa-88ec1232d2e6","order_by":9,"name":"Chan-Gi Pack","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Chan-Gi","middleName":"","lastName":"Pack","suffix":""},{"id":533826843,"identity":"99e0b62d-1121-439d-b132-62f064cd97c6","order_by":10,"name":"Hwon Heo","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Hwon","middleName":"","lastName":"Heo","suffix":""},{"id":533826844,"identity":"83cb3e5c-815f-4771-8d96-54db4b72fbd8","order_by":11,"name":"Kyung Won Kim","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kyung","middleName":"Won","lastName":"Kim","suffix":""},{"id":533826845,"identity":"37139548-b405-4497-b54e-221e61d9a8de","order_by":12,"name":"Jeong Kon Kim","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jeong","middleName":"Kon","lastName":"Kim","suffix":""},{"id":533826846,"identity":"96456369-ff87-49f0-824f-113621e0b81c","order_by":13,"name":"Yoonseok Choi","email":"","orcid":"","institution":"Gangneung Asan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoonseok","middleName":"","lastName":"Choi","suffix":""},{"id":533826847,"identity":"11b807bc-546d-4c3a-bbd3-a4ed3cf16b15","order_by":14,"name":"Dong-Cheol Woo","email":"","orcid":"https://orcid.org/0000-0001-8202-015X","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Dong-Cheol","middleName":"","lastName":"Woo","suffix":""}],"badges":[],"createdAt":"2025-09-30 05:43:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7747491/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7747491/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95065569,"identity":"7bd99bb0-ae8a-4245-8374-75b879fb98a2","added_by":"auto","created_at":"2025-11-04 01:28:38","extension":"tif","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14329638,"visible":true,"origin":"","legend":"","description":"","filename":"fig.1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/75563bb863237035d2e51db6.tif"},{"id":95065567,"identity":"a27b5485-8317-475b-83ee-4643536a1f14","added_by":"auto","created_at":"2025-11-04 01:28:38","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14541942,"visible":true,"origin":"","legend":"","description":"","filename":"fig.2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/e44929971bd436ba85f348b9.tif"},{"id":95222865,"identity":"f6465b65-7459-4473-ba53-8724eabf9862","added_by":"auto","created_at":"2025-11-05 16:21:16","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":13675918,"visible":true,"origin":"","legend":"","description":"","filename":"fig.3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/6432f099a00de5ea48ee9bbd.tif"},{"id":95065559,"identity":"d51814c3-cfa3-4ea6-a453-474f5c48bdf9","added_by":"auto","created_at":"2025-11-04 01:28:37","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16190,"visible":true,"origin":"","legend":"","description":"","filename":"mibiMIBID2500290.xml","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/c323c8f039aca2d1483c79f4.xml"},{"id":95222757,"identity":"8480e9a6-4cb0-4b0d-b1a2-a678081f5e5a","added_by":"auto","created_at":"2025-11-05 16:21:06","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1117,"visible":true,"origin":"","legend":"","description":"","filename":"MIBID25002907332.go.xml","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/4246aced5855c80de731a8f5.xml"},{"id":95065551,"identity":"85aadbcd-da68-4422-9a3f-f733805137ff","added_by":"auto","created_at":"2025-11-04 01:28:37","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":917,"visible":true,"origin":"","legend":"","description":"","filename":"MIBID2500290Import.xml","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/17d8c303c36e5c2442b6c5b4.xml"},{"id":95065553,"identity":"c8f4f230-2002-4919-b662-493d1e208d40","added_by":"auto","created_at":"2025-11-04 01:28:37","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":61788,"visible":true,"origin":"","legend":"","description":"","filename":"MIBID25002900enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/bfb9fc3e7c1cffd5a1a72705.xml"},{"id":95065564,"identity":"276dff93-3384-42f9-a42f-e73de0617923","added_by":"auto","created_at":"2025-11-04 01:28:38","extension":"tif","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14329638,"visible":true,"origin":"","legend":"","description":"","filename":"fig.1.tif","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/ce5f13a0cdf0f36ccaf49418.tif"},{"id":95065568,"identity":"14a6bcdc-ab92-4c9b-a856-93ae824cb7cc","added_by":"auto","created_at":"2025-11-04 01:28:38","extension":"tif","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14541942,"visible":true,"origin":"","legend":"","description":"","filename":"fig.2.tif","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/360594f7a170c3f49a13ec3c.tif"},{"id":95065565,"identity":"0502fdda-959b-4562-86a0-c16fdea44274","added_by":"auto","created_at":"2025-11-04 01:28:38","extension":"tif","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":13675918,"visible":true,"origin":"","legend":"","description":"","filename":"fig.3.tif","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/8e0fb1e47d7378d84b8200c2.tif"},{"id":95065566,"identity":"a6ab15da-79ce-424f-979a-c7b83591ff9b","added_by":"auto","created_at":"2025-11-04 01:28:38","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":94803,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/06f861f0e434e927045a6b6e.png"},{"id":95065560,"identity":"e8502847-df20-440c-9f6a-104983d0645a","added_by":"auto","created_at":"2025-11-04 01:28:38","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":90480,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/f4735727f186636c3cb77fad.png"},{"id":95223461,"identity":"5cdf0b63-91a7-4e78-86dc-8f2783cd76bd","added_by":"auto","created_at":"2025-11-05 16:22:18","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":175459,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/e6c5cd5db08939f3c16236cb.png"},{"id":95223043,"identity":"35ae0d6f-7a7a-4119-8c12-6fe9cbd8df7d","added_by":"auto","created_at":"2025-11-05 16:21:34","extension":"xml","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60544,"visible":true,"origin":"","legend":"","description":"","filename":"MIBID25002900structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/ee3c68b8aef01eb8bbdf4426.xml"},{"id":95065557,"identity":"ef24227c-b990-48c2-bcef-cac7cd6971da","added_by":"auto","created_at":"2025-11-04 01:28:37","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65606,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/fe060a7f71dc7ccb57697afc.html"},{"id":95065550,"identity":"a877c0cb-66d9-4ce3-9dae-b10ed6d2f346","added_by":"auto","created_at":"2025-11-04 01:28:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":295373,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic illustration of time-intensity curve in DCE-MRI. Quantitative parameters from DCE-MRI are derived from the signal intensity change curve over time. DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; AUC\u003csub\u003eTmax\u003c/sub\u003e, area under the curve from 0 to 6 min; SI\u003csub\u003emax\u003c/sub\u003e, maximum signal intensity; Tmax, time to maximum signal intensity; WiR, wash-in rate; WoR, wash-out rate.\u003c/p\u003e","description":"","filename":"fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/d48fddda9f00efa252bcf62d.png"},{"id":95223223,"identity":"8ac18a8f-0ffd-489f-8e16-a96e701dd4ee","added_by":"auto","created_at":"2025-11-05 16:21:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":317703,"visible":true,"origin":"","legend":"\u003cp\u003eIn vitro drug-drug interactions.\u003cstrong\u003e (a)\u003c/strong\u003e T1 and T2 mapping phantom images of Gd-EOB-DTPA obtained at various concentrations. \u003cstrong\u003e(b)\u003c/strong\u003e T1 and T2 mapping phantom images consisting of 3 × 10\u003csup\u003e6\u003c/sup\u003e Chang liver cells in various conditions after treatment for 6 h. \u003cstrong\u003e(c,d)\u003c/strong\u003e Comparison of MRI signal intensity measurements. Gd-EOB-DTPA, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid.\u003c/p\u003e","description":"","filename":"fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/5c65e6ab0e056659b4c4677c.png"},{"id":95223759,"identity":"58e4055f-99ba-449e-b70f-30568b0bc509","added_by":"auto","created_at":"2025-11-05 16:22:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":504060,"visible":true,"origin":"","legend":"\u003cp\u003eIn vivo drug-drug interactions.\u003cstrong\u003e (a)\u003c/strong\u003e Following the administration of various concentrations of sorafenib. DCE-MRI was performed 30 min later. \u003cstrong\u003e(b)\u003c/strong\u003e DCE-MRI was conducted 30 min and 4 h after administering 30 mg/kg of sorafenib. \u003cstrong\u003e(c,d)\u003c/strong\u003e RER was analyzed in T1-weighted DCE images. RER was analyzed in T1-weighted DCE images. \u003cstrong\u003e(e)\u003c/strong\u003e Representative MR images. \u003cstrong\u003e(f,g,h,i) \u003c/strong\u003eQuantification of DCE-MRI parameters Tmax, AUC\u003csub\u003e4\u003c/sub\u003e, WiR, and WoR in the liver. Sfb, sorafenib; i.v., intravenous; RER, relative enhancement rate; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging, AUC\u003csub\u003eTmax\u003c/sub\u003e, area under the curve from 0 to 6 min; Tmax, time to maximum; WiR, wash-in rate; WoR, wash-out rate.\u003c/p\u003e","description":"","filename":"fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/bb94a2e66743896e28caccf7.png"},{"id":95312415,"identity":"c5b992eb-03d0-4362-abda-2b466f7759aa","added_by":"auto","created_at":"2025-11-06 15:49:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1500131,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/25e9d229-6d3a-45a8-a3af-37326def44ec.pdf"},{"id":95065554,"identity":"0e689697-4d60-4f03-9fa4-4d6c4011d8b0","added_by":"auto","created_at":"2025-11-04 01:28:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":158365,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-7747491/v1/b5054d8f9469c1220ea0f593.docx"}],"financialInterests":"","formattedTitle":"Evaluating the effect of sorafenib on Gd-EOB-DTPA-mediated contrast enhancement: An experimental study using DCE-MRI","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is utilized for anatomical magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI (DCE-MRI) of the liver [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Its unique properties, particularly its high affinity for the Organic Anion Transporting Protein (OATP) family specifically OATP1B1 and OATP1B3, which are prominently expressed in the liver enable Gd-EOB-DTPA-enhanced MRI to provide detailed anatomical images of the liver and its vasculature [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSorafenib is a multi-kinase inhibitor that targets several tyrosine kinase pathways, including Raf, VEGFR, and PDGFR. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Given that these pathways are intricately involved in tumor cell proliferation and angiogenesis, sorafenib has garnered significant attention as an effective therapeutic agent for various cancers [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] However, multiple studies have explored the interaction between sorafenib and OATPs, revealing that sorafenib can modify the transport activities of OATP1B1 and OATP1B3 [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, sorafenib affects OATP transport activity in hepatocytes, leading to alterations in the influx and efflux of Gd-EOB-DTPA, which may result in changes to the contrast observed in liver MRI when sorafenib is administered to patients with hepatocellular carcinoma.\u003c/p\u003e\u003cp\u003eNotably, numerous studies have concurrently utilized sorafenib and Gd-EOB-DTPA to test their respective hypotheses [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, most of these studies focused on the individual functionalities of sorafenib and Gd-EOB-DTPA without quantifying the extent to which sorafenib affects Gd-EOB-DTPA over time and dosage. Furthermore, although previous investigations regarding the effects of various tyrosine kinase inhibitors on Gd-EOB-DTPA uptake indicated negligible effects, sorafenib was not included in those experiments [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eChang liver cells, which were used as an in vitro model in this study, have been widely reported to originate from HeLa cells rather than hepatocytes. Despite this origin, the use of Chang liver cells was deemed suitable for this study, as the expression of OATP transporters was confirmed by qPCR and immunofluorescence analysis [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Considering that the primary objective of this study was to evaluate OATP-mediated drug-drug interactions rather than hepatocyte-specific metabolic functions, the cell origin is unlikely to have influenced the validity of the experimental outcomes.\u003c/p\u003e\u003cp\u003eTherefore, the purpose of this study was to assess and quantify the effect of sorafenib on Gd-EOB-DTPA-induced contrast enhancements.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eMR phantom preparations\u003c/h2\u003e\u003cp\u003eSerially diluted Gd-EOB-DTPA (Primovist\u0026reg;, BayerPharma, Berlin, Germany) solutions were prepared as reference phantoms in 0.2-mL tubes at concentrations of 0, 5, 32.5, and 125 \u0026micro;M.\u003c/p\u003e\u003cp\u003eChang liver cells were cultured in Dulbecco's Modified Eagle Medium (Gibco, Grand Island, NY, USA) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin solution. The cells were incubated at 37\u0026deg;C in a humidified atmosphere containing 5% CO\u003csub\u003e2\u003c/sub\u003e. For the cell phantoms, the cells were treated with Gd-EOB-DTPA for 6 h, sorafenib (SML2633, Sigma-Aldrich, St. Louis, MO, USA), or a combination of both agents at the following concentrations: Gd-EOB-DTPA at 5 mM or 10 mM, and sorafenib at 10 mM or 30 mM. The cells were subsequently washed twice using phosphate buffered saline, and 3 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e cells were harvested and transferred to 0.2-mL tubes. After centrifugation at 500 \u003cem\u003eg\u003c/em\u003e for 10 min, the supernatants were carefully removed, and the tubes were sealed with 1% agarose gel.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eIn vitro MRI and relaxivity measurements\u003c/h3\u003e\n\u003cp\u003eFor the measurements of the MR relaxivities (r1 and r2), T1 and T2 mapping images were acquired using the following MR parameters: (1) T1 mapping with eight inversion times (TI) = [20, 100, 200, 400, 800, 1000, 2000, 4000] ms, repetition time (TR)\u0026thinsp;=\u0026thinsp;5000 ms, echo time (TE)\u0026thinsp;=\u0026thinsp;7.10 ms, average\u0026thinsp;=\u0026thinsp;1, slice thickness\u0026thinsp;=\u0026thinsp;1.0 mm, matrix size\u0026thinsp;=\u0026thinsp;96 \u0026times; 96, and field of view (FOV)\u0026thinsp;=\u0026thinsp;70 \u0026times; 60 mm\u003csup\u003e2\u003c/sup\u003e; (2) T2 mapping with 15 TEs = [10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150] ms, TR\u0026thinsp;=\u0026thinsp;3000 ms, average\u0026thinsp;=\u0026thinsp;1, slice thickness\u0026thinsp;=\u0026thinsp;1.0 mm, matrix size\u0026thinsp;=\u0026thinsp;96 \u0026times; 96, and FOV\u0026thinsp;=\u0026thinsp;70 \u0026times; 60 mm\u003csup\u003e2\u003c/sup\u003e. T1 and T2 values were analyzed by selecting regions of interest in different tubes. In vitro MRI was conducted using a 9.4-T magnet (Agilent, Inc., Santa Clara, CA, USA) and MR relaxivities were calculated using Asan J software, an analytic software derived from ImageJ (NIH, Bethesda, MA, USA).\u003c/p\u003e\n\u003ch3\u003eAnimals\u003c/h3\u003e\n\u003cp\u003eSixteen male Sprague\u0026ndash;Dawley rats (n\u0026thinsp;=\u0026thinsp;16; 8 weeks old) were obtained from Orient Animal Laboratory (Seoul, South Korea) and randomly divided into experimental groups, each containing four animals. All rats were maintained at a controlled room temperature of 22\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C, humidity of 55\u0026thinsp;\u0026plusmn;\u0026thinsp;5%, and a 12:12-hour light-dark cycle. All procedures received approval from the Institutional Animal Care and Use Committee of Asan Medical Center (IACUC No. 2024-10-024), and experiments were conducted according to relevant guidelines for ethical animal experimentation. Sorafenib was dissolved in a mixture of 1% dimethyl sulfoxide and 40% sulfobutyl ether β-Cyclodextrin (Thermo Fisher Scientific, Sunnyvale, CA, USA) in normal saline, and the solution was filtered through a 0.45-\u0026micro;m membrane filter prior to administration. Sorafenib was administered intravenously at doses of 10 or 30 mg/kg just before MRI acquisition.\u003c/p\u003e\n\u003ch3\u003eIn vivo MRI and analyses\u003c/h3\u003e\n\u003cp\u003eAnimal MRIs were conducted using a 9.4-T magnet (Agilent, Inc., Santa Clara, CA, USA) equipped with a 64-mm transmit/receive volume coil. All animals were maintained under respiratory anesthesia with a 1.5\u0026ndash;2% isoflurane/air mixture, and their body temperature was regulated at 37.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u0026deg;C using an air heater system. The respiratory rate was continuously monitored to allow for adjustments in anesthetic concentration. T1-weighted DCE-MRI scans were acquired following the intravenous administration of 25 \u0026micro;mol/kg Gd-EOB-DTPA after 120 s. The specific imaging parameters were as follows: TR/TE\u0026thinsp;=\u0026thinsp;70/2.34 ms, flip angle\u0026thinsp;=\u0026thinsp;35\u0026deg;, average\u0026thinsp;=\u0026thinsp;1, matrix size\u0026thinsp;=\u0026thinsp;96 \u0026times; 96, FOV\u0026thinsp;=\u0026thinsp;50 \u0026times; 50 mm\u0026sup2;, total scan time\u0026thinsp;=\u0026thinsp;44 min 48 s, and total number of images\u0026thinsp;=\u0026thinsp;400.\u003c/p\u003e\u003cp\u003eAnimal MRI data were analyzed using Asan J software, which integrates ImageJ and MATLAB (The MathWorks, Natick, MA, USA). Regions of interest were randomly placed within the liver, avoiding visible blood vessels, and subsequent measurements were taken. The RER was calculated using the equation RER = [{SI(t)\u0026thinsp;\u0026minus;\u0026thinsp;SI(0)} / SI(0)] \u0026times; 100 (%), where SI(t) represents the signal intensity of the liver at time t, and SI(0) denotes the average signal intensity prior to Gd-EOB-DTPA injection. Various quantitative parameters were derived from the signal intensity curve, including time to maximum (Tmax), area under the curve from 0 to 6 min (AUC\u003csub\u003eTmax\u003c/sub\u003e), wash-in rate slope (WiR), and wash-out rate slope (WoR), as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were performed using IBM SPSS for Windows version 21.0 (IBM Corp., Armonk, NY, USA). Various MR values were compared using a one-way analysis of variance with Tukey\u0026rsquo;s post-hoc test. A p-value of less than 0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eT1 and T2 relaxation times of Gd-EOB-DTPA and sorafenib-treated cells\u003c/h2\u003e\u003cp\u003ePhantom images were first acquired to determine the reference T1 and T2 relaxation times of various concentrations of Gd-EOB-DTPA (0, 5, 32.5, and 125 \u0026micro;M). As the concentration of Gd-EOB-DTPA increased, T1 and T2 values decreased. The T1 and T2 relaxation times were as follows: 0 \u0026micro;M, 2887.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 ms; 5 \u0026micro;M, 2437.7\u0026thinsp;\u0026plusmn;\u0026thinsp;24.4 ms; 32.5 \u0026micro;M, 1598.0\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9 ms; and 125 \u0026micro;M, 703.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6 ms; vs. 0 \u0026micro;M, 1441.2\u0026thinsp;\u0026plusmn;\u0026thinsp;35.1 ms; 5 \u0026micro;M, 1393.0\u0026thinsp;\u0026plusmn;\u0026thinsp;57.6 ms; 32.5 \u0026micro;M, 1061.8\u0026thinsp;\u0026plusmn;\u0026thinsp;26.4 ms; and 125 \u0026micro;M, 501.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7 ms; respectively; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA\u0026ndash;D). Subsequently, T1 and T2 relaxation times were measured using Chang liver cell phantoms to evaluate the impact of sorafenib on the uptake of Gd-EOB-DTPA in these cells. Notably, T1 and T2 values decreased following treatment with Gd-EOB-DTPA (5 mM and 10 mM) compared to untreated cells. However, when the cells were treated with both Gd-EOB-DTPA (10 mM) and sorafenib (10 \u0026micro;M or 30 \u0026micro;M), T1 and T2 values increased, suggesting that sorafenib influenced the amount of Gd-EOB-DTPA present in the cells. The degree of interference in T1 and T2 shortening intensified with increasing concentrations of sorafenib. The T1 and T2 values for each experimental condition were as follows: Untreated Group (T1: 1525.7\u0026thinsp;\u0026plusmn;\u0026thinsp;83.9 ms, T2: 70.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 ms), Gd-EOB-DTPA 5 mM Group (T1: 916.7\u0026thinsp;\u0026plusmn;\u0026thinsp;421.1 ms, T2: 42.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8 ms), Gd-EOB-DTPA 10 mM Group (T1: 659.8\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1 ms, T2: 31.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0 ms), Gd-EOB-DTPA 10 mM\u0026thinsp;+\u0026thinsp;Sfb 10 \u0026micro;M Group (T1: 787.0\u0026thinsp;\u0026plusmn;\u0026thinsp;897.7 ms, T2: 52.3\u0026thinsp;\u0026plusmn;\u0026thinsp;51.6 ms), and Gd-EOB-DTPA 10 mM\u0026thinsp;+\u0026thinsp;Sfb 30 \u0026micro;M Group (T1: 1008.1\u0026thinsp;\u0026plusmn;\u0026thinsp;98.6 ms, T2: 83.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6 ms; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB\u0026ndash;D).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003e\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003e\u003cem\u003eEvaluating the effects of sorafenib on contrast enhancement in rats\u003c/em\u003e\u003c/div\u003e\u003cp\u003eWe investigated the effects of sorafenib on contrast enhancement in SD rats using varying concentrations (vehicle, 10 mg/kg, 30 mg/kg) and time points (30 min and 4 h post-administration; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-B). DCE-MRI time-intensity curves were analyzed to assess both concentration- and time-dependent changes (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC\u0026ndash;E). The time to maximum signal intensity (Tmax) exhibited a dose-dependent increase in the sorafenib-treated groups compared to the vehicle group, with a partial recovery observed in the 4-h group (Tmax: 16.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80 for vehicle, 12.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22 for Sfb 10 mg/kg at 30 min, 8.52\u0026thinsp;\u0026plusmn;\u0026thinsp;3.93 for Sfb 30 mg/kg at 30 min, and 12.72\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62 for Sfb 30 mg/kg at 4 h; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eF). The area under the curve until Tmax (AUC\u003csub\u003eTmax\u003c/sub\u003e) demonstrated a concentration-dependent decrease, with signs of recovery at 4 h post-administration (AUC\u003csub\u003eTmax\u003c/sub\u003e: 16.20\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80 for vehicle, 12.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22 for Sfb 10 mg/kg, 8.52\u0026thinsp;\u0026plusmn;\u0026thinsp;3.93 for Sfb 30 mg/kg, and 12.72\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62 for Sfb 30 mg/kg at 4 h; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eG). The WiR exhibited a similar pattern, revealing reduced values in sorafenib-treated groups and partial recovery at 4 h (WiR: 1.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32 for vehicle, 0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10 for Sfb 10 mg/kg, 0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34 for Sfb 30 mg/kg, and 0.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41 for Sfb 30 mg/kg at 4 h; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eH). Conversely, the WoR increased in sorafenib-treated groups, indicating slower contrast clearance, with partial normalization observed at 4 h (WoR: -0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 for vehicle, -0.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 for Sfb 10 mg/kg, -0.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 for Sfb 30 mg/kg, and \u0026minus;\u0026thinsp;0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 for Sfb 30 mg/kg at 4 h; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eI). Collectively, these findings demonstrate the dose- and time-dependent effects of sorafenib on contrast enhancement parameters in vivo.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study aimed to investigate the effects of sorafenib treatment on Gd-EOB-DTPA-induced contrast enhancements at both cellular and animal levels. Specifically, we utilized MRI and DCE-MRI to obtain quantified values that represent the impact of sorafenib on Gd-EOB-DTPA-induced contrast enhancements.\u003c/p\u003e\u003cp\u003eAlterations in T1 and T2 values from the cell phantom experiment indicate potential interference with Gd-EOB-DTPA uptake when exposed to sorafenib. These results are consistent with previous studies indicating that sorafenib interacts with OATPs, particularly OATP1B1, and inhibits their function [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Furthermore, quantitative data from various DCE-MRI parameters, including RER, Tmax, AUC\u003csub\u003eTmax\u003c/sub\u003e, WiR, and WoR, support the notion of sorafenib-mediated interference with cellular uptake of the contrast agent. Notably, we observed a time-dependent recovery in RER, as evidenced by the comparative analysis of 30-min and 4-h DCE-MRI scans; however, the dose-dependent analysis indicated a decrease at the 30-min mark. Therefore, the effects of sorafenib on Gd-EOB-DTPA uptake may be reversible over time.\u003c/p\u003e\u003cp\u003eThere were several limitations to this study. First, we utilized Chang liver cells, which are derived from HeLa cells rather than hepatocytes. However, these cells were selected because previous research has demonstrated their expression of OATP transporters (Supplementary Fig.\u0026nbsp;1) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Given that the primary aim was to investigate transporter-mediated drug-drug interactions rather than functions specific to hepatocytes, employing these cells was deemed suitable for our experiment. Additional studies with primary hepatocytes could provide further validation of our findings. However, the use of primary hepatocytes was not feasible in this study due to the large number of cells required for cell phantom preparation. Second, while sorafenib is typically administered orally in clinical practice, our study utilized intravenous administration. This difference in the route of administration may influence the drug\u0026rsquo;s pharmacokinetics and, consequently, its effects on Gd-EOB-DTPA uptake. Third, in clinical settings, the recommended daily oral dose of sorafenib for adult patients is 800 mg (400 mg twice daily) [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Assuming an average adult weight of 70 kg, this translates to approximately 11.4 mg/kg per day. In contrast, our study employed intravenous doses of 10 and 30 mg/kg. Therefore, the doses of sorafenib administered intravenously in our experimental setting were significantly higher than those typically used in clinical practice, even when accounting for differences in bioavailability between oral and intravenous routes. This higher dosage was selected to ensure observable effects in our experimental model and to account for potential differences in drug metabolism between humans and animal models. Consequently, the elevated doses used in our experiments could lead to more substantial effects on Gd-EOB-DTPA uptake compared to standard clinical dosing. Therefore, while our results provide valuable insights to the potential interactions between sorafenib and Gd-EOB-DTPA, the magnitude of these effects in clinical practice may differ due to the lower doses routinely administered to patients.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study presents quantified experimental evidence from both in vitro and in vivo studies, demonstrating that sorafenib interferes with the cellular uptake of Gd-EOB-DTPA. These findings underscore the necessity of considering drug-drug interactions in liver MRI scans, particularly in patients undergoing targeted kinase inhibitor therapy. Further research is needed to elucidate the clinical implications of these interactions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Contributions:\u0026nbsp;\u003c/strong\u003eConceptualization: YC, DCW. Data curation: ET, CHH, JKR, IJB, CGP. Formal analysis: CYJ. Investigation: CYJ. Methodology: DWL, CWW, YSS. Project administration: YC. Resources: ET, YC, DCW. Software: DWL, CWW, YSS. Supervision: DCW. Validation: JHC, CHH, JKR, IJB, CGP, KWK, JKK. Visualization: CYJ, HH. Writing\u0026mdash;original draft: CYJ, YC, DCW. Writing\u0026mdash;review and editing: DWL, CWW, YSS, JHC, ET, CHH, JKR, IJB, CGP, HH, KWK, JKK, YC, DCW. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eThis research was supported by the National Research Foundation of Korea (NRF) (Grant No.2022R1Z1A1A01066589 and 2022R1C1C2008801).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThe study was approved by the Institutional Animal Care and Use Committee of Asan Medical Center (IACUC No. 2024-10-024)\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLiu HF, Wang Q, Du YN et al (2020) Dynamic contrast-enhanced MRI with Gd-EOB-DTPA for the quantitative assessment of early-stage liver fibrosis induced by carbon tetrachloride in rabbits. Magn Reson Imaging 70:57\u0026ndash;63\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSaito K, Ledsam J, Sourbron S et al (2013) Assessing liver function using dynamic Gd-EOB-DTPA-enhanced MRI with a standard 5-phase imaging protocol. J Magn Reson Imaging 37(5):1109\u0026ndash;1114\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen BB, Hsu CY, Yu CW et al (2012) Dynamic contrast-enhanced magnetic resonance imaging with Gd-EOB-DTPA for the evaluation of liver fibrosis in chronic hepatitis patients. Eur Radiol 22(1):171\u0026ndash;180\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMurase K, Kashiwagi N, Tomiyama N (2022) Quantitative evaluation of simultaneous spatial and temporal regularization in dynamic contrast-enhanced MRI of the liver using Gd-EOB-DTPA. Magn Reson Imaging 88:25\u0026ndash;37\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJia J, Puls D, Oswald S et al (2014) Characterization of the intestinal and hepatic uptake/efflux transport of the magnetic resonance imaging contrast agent gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid. Invest Radiol 49(2):78\u0026ndash;86\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeonhardt M, Keiser M, Oswald S et al (2010) Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos 38(7):1024\u0026ndash;1028\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHaimerl M, Verloh N, Zeman F et al (2017) Gd-EOB-DTPA-enhanced MRI for evaluation of liver function: Comparison between signal-intensity-based indices and T1 relaxometry. Sci Rep 7(1):43347\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNassif A, Jia J, Keiser M et al (2012) Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging. Radiology 264(3):741\u0026ndash;750\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLaitinen A, Niemi M (2011) Frequencies of single-nucleotide polymorphisms of SLCO1A2, SLCO1B3 and SLCO2B1 genes in a Finnish population. Basic Clin Pharmacol Toxicol 108(1):9\u0026ndash;13\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTang WW, Chen ZY, Zhang WL et al (2020) The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Therapy 5(1):87\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWilhelm S, Carter C, Lynch M et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5(10):835\u0026ndash;844\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeng GL, Luo Y, Zhang Q, Zeng F, Xu J, Zhu JQ (2020) Sorafenib and radioiodine-refractory differentiated thyroid cancer (RR-DTC): a systematic review and meta-analysis. Endocrine 68(1):56\u0026ndash;63\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBahman A, Abaza MS, Khoushaish S, Al-Attiyah RJ (2023) Therapeutic efficacy of sorafenib and plant-derived phytochemicals in human colorectal cancer cells. BMC Complement Med Ther 23(1):210\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRebaz MA, Sami SO, Fahmi HK et al (2024) Efficacy of Sorafenib in the Management of Non-Small Cell Lung Cancer: A Systematic Review. Barw Med J 2(2):31\u0026ndash;38\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHu S, Mathijssen RH, de Bruijn P, Baker SD, Sparreboom A (2014) Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations. Br J Cancer 110(4):894\u0026ndash;898\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWen J, Zhao M (2021) OATP1B1 Plays an Important Role in the Transport and Treatment Efficacy of Sorafenib in Hepatocellular Carcinoma. Dis Markers 2021:9711179\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHayden ER, Chen M, Pasquariello KZ et al (2021) Regulation of OATP1B1 Function by Tyrosine Kinase-mediated Phosphorylation. Clin Cancer Res 27(15):4301\u0026ndash;4310\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSaito K, Ledsam J, Sugimoto K, Sourbron S, Araki Y, Tokuuye K (2018) DCE-MRI for Early Prediction of Response in Hepatocellular Carcinoma after TACE and Sorafenib Therapy: A Pilot Study. J Belg Soc Radiol 102(1):40\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDong Z, Huang K, Liao B et al (2019) Prediction of sorafenib treatment-related gene expression for hepatocellular carcinoma: preoperative MRI and histopathological correlation. Eur Radiol 29:2272\u0026ndash;2282\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e\u0026Ouml;cal O, R\u0026ouml;ssler D, Gasbarrini A et al (2022) Gadoxetic acid uptake as a molecular imaging biomarker for sorafenib resistance in patients with hepatocellular carcinoma: a post hoc analysis of the SORAMIC trial. J Cancer Res Clin Oncol 148(9):2487\u0026ndash;2496\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuppertz A, Breuer J, Fels LM et al (2011) Evaluation of Possible Drug-Drug Interaction Between Gadoxetic Acid and Erythromycin as an Inhibitor of Organic Anion Transporting Peptides (OATP). J Magn Reson Imaging 33(2):409\u0026ndash;416\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNakamura Y, Hirokawa Y, Kitamura S et al (2013) Effect of lapatinib on hepatic parenchymal enhancement on gadoxetate disodium (EOB)-enhanced MRI scans of the rat liver. Japanese J Radiol 31(6):386\u0026ndash;392\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePeng JF, Liu L, Guo CX et al (2015) Role of miR-511 in the Regulation of OATP1B1 Expression by Free Fatty Acid. Biomol Ther (Seoul) 23(5):400\u0026ndash;406\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu CC, Chen WK, Chiang JH et al (2018) cDNA Microarray Analysis and Influx Transporter OATP1B1 in Liver Cells After Exposure to Gadoxetate Disodium, a Gadolinium-based Contrast Agent in MRI Liver Imaging. In Vivo 32(3):677\u0026thinsp;\u0026ndash;\u0026thinsp;84\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLlovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in Advanced Hepatocellular Carcinoma (vol 359, pg 378, 2008). New England Journal of Medicine 359(4):2508\u0026ndash;2508\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEscudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125\u0026ndash;134\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-imaging-and-biology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mibi","sideBox":"Learn more about [Molecular Imaging and Biology](http://link.springer.com/journal/11307)","snPcode":"11307","submissionUrl":"https://www.editorialmanager.com/mibi/default2.aspx","title":"Molecular Imaging and Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Sorafenib, Gd-EOB-DTPA, Cellular Uptake Inhibition, Drug Interactions, DCE-MRI","lastPublishedDoi":"10.21203/rs.3.rs-7747491/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7747491/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eDespite the potential impact of sorafenib on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-mediated contrast enhancements, attempts to assess these effects are rare. This study aimed to investigate the interaction between Sorafenib and Gd-EOB-DTPA by quantifying the T1 and T2 relaxation times and the relative enhancement rates (RERs) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the liver.\u003c/p\u003e\u003ch2\u003eProcedures:\u003c/h2\u003e\u003cp\u003eThe effects on contrast enhancement were assessed using MRI with Chang liver cells and SD rats. MR phantom images were obtained after treating cells with varying dosages of Gd-EOB-DTPA (5, 10 mM) and sorafenib (10, 30 \u0026micro;M) to evaluate MR relaxivities. For the animal study, DCE-MRI was performed following intravenous administration of 25 \u0026micro;mol/kg Gd-EOB-DTPA and two different doses of sorafenib (10, 30 mg/kg). RER was analyzed to evaluate sorafenib's effects on Gd-EOB-DTPA uptake in the liver.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003ePhantom experiments demonstrated alterations in T1 and T2 values, with a tendency towards shortening disrupted by the addition of Sorafenib to Gd-EOB-DTPA-treated Chang liver cells. The RERs of DCE-MRI in the liver exhibited a dose-dependent decrease following sorafenib administration, with recovery observed after 4 h.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eOur results provide quantitative information on sorafenib-mediated interference with Gd-EOB-DTPA-induced contrast enhancement and offer experimental evidence suggesting the possibility of drug-drug interactions between sorafenib and Gd-EOB-DTPA. Although further research is needed to fully elucidate the impact of these interactions, caution is warranted when using these two agents concurrently for liver MRI.\u003c/p\u003e","manuscriptTitle":"Evaluating the effect of sorafenib on Gd-EOB-DTPA-mediated contrast enhancement: An experimental study using DCE-MRI","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-04 01:28:32","doi":"10.21203/rs.3.rs-7747491/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revisions","date":"2026-03-06T02:01:46+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-10-24T00:52:17+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-23T08:30:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-20T14:50:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Imaging and Biology","date":"2025-10-17T06:22:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-imaging-and-biology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mibi","sideBox":"Learn more about [Molecular Imaging and Biology](http://link.springer.com/journal/11307)","snPcode":"11307","submissionUrl":"https://www.editorialmanager.com/mibi/default2.aspx","title":"Molecular Imaging and Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5daf7d99-9386-4524-a112-fedfd88afe32","owner":[],"postedDate":"November 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T14:31:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-04 01:28:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7747491","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7747491","identity":"rs-7747491","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}