Transport and Phosphorylation Kinetics of Zidovudine in the Chinese Population: Implications for Individualized Antiretroviral Therapy

Transport and Phosphorylation Kinetics of Zidovudine in the Chinese Population: Implications for Individualized Antiretroviral Therapy | 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 Article Transport and Phosphorylation Kinetics of Zidovudine in the Chinese Population: Implications for Individualized Antiretroviral Therapy Fang Tang, Shan Ji, Xiujun Lai, Tao Yan, Jie Peng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7647877/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted 9 You are reading this latest preprint version Abstract Background and Purpose Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor, exerts its antiviral effect through intracellular conversion to AZT-triphosphate(AZT-TP), with therapeutic efficacy and toxicity closely linked to intracellular AZT-TP levels rather than plasma AZT concentrations. However, research on AZT transport and phosphorylation in the Chinese population is scarce, and the relationship between transporter/kinase protein expression and AZT intracellular metabolism remains unclear. This study aimed to characterize the cellular transport and phosphorylation kinetics of AZT in Chinese individuals, develop a pharmacokinetic model linking plasma AZT to intracellular AZT-TP, and explore the impact of transporter expression, to support personalized antiretroviral therapy. Experimental Approach In vitro experiments used Molt-4 and HUVEC cells. Cytotoxicity was assessed via CCK-8 assay. Concentration-dependent studies incubated cells with 0–200 μM AZT for 12 hours, while time-course studies exposed cells to 100 μM AZT for 0.5–36 hours, quantifying intracellular AZT and metabolites via HPLC-MS/MS. In vivo, six healthy Chinese volunteers received a single 600 mg oral AZT dose, with blood samples collected over 10 hours to measure plasma AZT and intracellular metabolites in peripheral blood mononuclear cells (PBMCs). A two-compartment pharmacokinetic model was developed, and ABC transporter expression was quantified using HPLC-MS/MS. Key Results In vitro, AZT showed negligible cytotoxicity at 50 μM for 36 hours. Intracellular AZT, zidovudine monophosphate (AZT-MP), zidovudine diphosphat (AZT-DP), and zidovudine triphosphate (AZT-TP) increased linearly with extracellular AZT (0–200 μM), with time-course studies showing rapid initial accumulation followed by plateauing, and cell-type differences in kinetics. In vivo, plasma AZT had a Tmax of 0.62 ± 0.20 hours and T1/2 of 1.95 ± 0.20 hours. Intracellular AZT-TP in PBMCs exhibited marked inter-individual variability. The pharmacokinetic model parameters differed from non-Chinese cohorts. ABCB1 and ABCG2 expression strongly correlated with AZT efflux, while ABCC1 did not. Conclusion and Implications This study clarifies AZT's transport and phosphorylation kinetics in Chinese subjects, showing that intracellular AZT-TP levels, linked to efficacy and toxicity, are influenced by plasma concentrations, transporter/kinase activity, and protein expression. The findings highlight the role of ABCB1 and ABCG2 in AZT efflux and support the need for individualized dosing based on intracellular metabolite levels and transporter expression, advancing personalized antiretroviral therapy in the Chinese population. Biological sciences/Cell biology Health sciences/Diseases Biological sciences/Drug discovery Zidovudine Phosphorylation Zidovudine monophosphate Zidovudine diphosphate Zidovudine triphosphate Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 02 Dec, 2025 Reviews received at journal 01 Dec, 2025 Reviewers agreed at journal 13 Nov, 2025 Reviews received at journal 11 Nov, 2025 Reviewers agreed at journal 30 Oct, 2025 Reviewers invited by journal 21 Oct, 2025 Editor assigned by journal 06 Oct, 2025 Submission checks completed at journal 29 Sep, 2025 First submitted to journal 29 Sep, 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. 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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-7647877","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":537549043,"identity":"34054ffd-3341-4f52-aa06-73a6e5ad12d2","order_by":0,"name":"Fang Tang","email":"","orcid":"","institution":"The Affiliated Nanhua Hospital, Department of Pharmacy, Hengyang Medical School, University of South China","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Tang","suffix":""},{"id":537549044,"identity":"e6576d08-31fe-4c21-be6f-8711bc5419bf","order_by":1,"name":"Shan Ji","email":"","orcid":"","institution":"School 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Therapy","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Zidovudine, Phosphorylation, Zidovudine monophosphate, Zidovudine diphosphate, Zidovudine triphosphate","lastPublishedDoi":"10.21203/rs.3.rs-7647877/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7647877/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and Purpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZidovudine (AZT), a nucleoside reverse transcriptase inhibitor, exerts its antiviral effect through intracellular conversion to AZT-triphosphate(AZT-TP), with therapeutic efficacy and toxicity closely linked to intracellular AZT-TP levels rather than plasma AZT concentrations. However, research on AZT transport and phosphorylation in the Chinese population is scarce, and the relationship between transporter/kinase protein expression and AZT intracellular metabolism remains unclear. This study aimed to characterize the cellular transport and phosphorylation kinetics of AZT in Chinese individuals, develop a pharmacokinetic model linking plasma AZT to intracellular AZT-TP, and explore the impact of transporter expression, to support personalized antiretroviral therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExperimental Approach\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn vitro experiments used Molt-4 and HUVEC cells. Cytotoxicity was assessed via CCK-8 assay. Concentration-dependent studies incubated cells with 0–200 μM AZT for 12 hours, while time-course studies exposed cells to 100 μM AZT for 0.5–36 hours, quantifying intracellular AZT and metabolites via HPLC-MS/MS. In vivo, six healthy Chinese volunteers received a single 600 mg oral AZT dose, with blood samples collected over 10 hours to measure plasma AZT and intracellular metabolites in peripheral blood mononuclear cells (PBMCs). A two-compartment pharmacokinetic model was developed, and ABC transporter expression was quantified using HPLC-MS/MS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKey Results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn vitro, AZT showed negligible cytotoxicity at 50 μM for 36 hours. Intracellular AZT, zidovudine monophosphate (AZT-MP), zidovudine diphosphat (AZT-DP), and zidovudine triphosphate (AZT-TP) increased linearly with extracellular AZT (0–200 μM), with time-course studies showing rapid initial accumulation followed by plateauing, and cell-type differences in kinetics. In vivo, plasma AZT had a Tmax of 0.62 ± 0.20 hours and T1/2 of 1.95 ± 0.20 hours. Intracellular AZT-TP in PBMCs exhibited marked inter-individual variability. The pharmacokinetic model parameters differed from non-Chinese cohorts. ABCB1 and ABCG2 expression strongly correlated with AZT efflux, while ABCC1 did not.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion and Implications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study clarifies AZT's transport and phosphorylation kinetics in Chinese subjects, showing that intracellular AZT-TP levels, linked to efficacy and toxicity, are influenced by plasma concentrations, transporter/kinase activity, and protein expression. The findings highlight the role of ABCB1 and ABCG2 in AZT efflux and support the need for individualized dosing based on intracellular metabolite levels and transporter expression, advancing personalized antiretroviral therapy in the Chinese population.\u003c/p\u003e","manuscriptTitle":"Transport and Phosphorylation Kinetics of Zidovudine in the Chinese Population: Implications for Individualized Antiretroviral Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-01 18:35:57","doi":"10.21203/rs.3.rs-7647877/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-02T05:55:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-01T13:29:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271435360800630219481875334390822890859","date":"2025-11-13T07:24:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-11T19:12:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"181085716865246773693458299038383453987","date":"2025-10-30T10:51:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-22T02:41:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-06T12:52:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-29T09:29:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-09-29T09:16:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"00a01b2e-b566-47e1-8957-52dc1ef5eeb7","owner":[],"postedDate":"November 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":57168198,"name":"Biological sciences/Cell biology"},{"id":57168199,"name":"Health sciences/Diseases"},{"id":57168200,"name":"Biological sciences/Drug discovery"}],"tags":[],"updatedAt":"2026-04-27T16:09:01+00:00","versionOfRecord":{"articleIdentity":"rs-7647877","link":"https://doi.org/10.1038/s41598-026-49905-1","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-04-24 15:59:08","publishedOnDateReadable":"April 24th, 2026"},"versionCreatedAt":"2025-11-01 18:35:57","video":"","vorDoi":"10.1038/s41598-026-49905-1","vorDoiUrl":"https://doi.org/10.1038/s41598-026-49905-1","workflowStages":[]},"version":"v1","identity":"rs-7647877","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7647877","identity":"rs-7647877","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}