An in Vitro Digestion Test That Reflects Rat Intestinal Conditions To Probe the Importance of Formulation Digestion vs First Pass Metabolism in Danazol Bioavailability from Lipid Based Formulations

Mette U. Anby, Tri‐Hung Nguyen, Yan Yan Yeap, Orlagh M. Feeney, Hywel D. Williams, Hassan Benameur, Colin W. Pouton, Christopher J. H. Porter
In: Molecular Pharmaceutics · 2014 · vol. 11(11) , pp. 4069–4083 · doi:10.1021/mp500197b · PMID:25265395 · W2329755406
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This study investigated how formulation digestion and first-pass metabolism affect danazol bioavailability from lipid-based formulations in rats, finding first-pass metabolism to be the primary bioavailability limitation.

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The paper evaluated how gastrointestinal processing and first-pass metabolism affect the oral bioavailability of danazol in rats after administration of self-emulsifying drug delivery systems (SEDDS) and related lipid formulations. Danazol absolute bioavailability was measured following oral and intraduodenal dosing of multiple medium-chain (LFCS class IIIA) formulations with different drug loadings, compared with a lipid-free class IV formulation, and the experiments included presence versus absence of the metabolism inhibitor ABT (1-aminobenzotriazole). The results showed low danazol absolute bioavailability after oral dosing, while intraduodenal dosing supported higher exposure, and ABT pretreatment changed the observed fraction absorbed in a manner consistent with in vitro digestion models indicating less precipitation during formulation digestion under rat GI conditions. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

The impact of gastrointestinal (GI) processing and first pass metabolism on danazol oral bioavailability (BA) was evaluated after administration of self-emulsifying drug delivery systems (SEDDS) in the rat. Danazol absolute BA was determined following oral and intraduodenal (ID) administration of LFCS class IIIA medium chain (MC) formulations at high (SEDDSH-III) and low (SEDDSL-III) drug loading and a lipid free LFCS class IV formulation (SEDDS-IV). Experiments were conducted in the presence and absence of ABT (1-aminobenzotriazole) to evaluate the effect of first pass metabolism. A series of modified in vitro lipolysis tests were developed to better understand the in vivo processing of SEDDS in the rat. Danazol BA was low (<13%) following oral and ID administration of either SEDDS. Increasing drug loading, ID rather than oral administration, and administration of SEDDS-IV rather than SEDDS-III led to higher oral BA. After pretreatment with ABT, however, danazol oral BA significantly increased (e.g., 60% compared to 2% after administration of SEDDSL-III), no effect was observed on increasing drug loading, and differences between SEDDS-III and -IV were minimal. In vitro digestion models based on the lower enzyme activity and lower dilution conditions expected in the rat resulted in significantly reduced danazol precipitation from SEDDS-III or SEDDS-IV on initiation of digestion. At the doses administered here (4-8 mg/kg), the primary limitation to danazol oral BA in the rat was first pass metabolism, and the fraction absorbed was >45% after oral administration of SEDDS-III or SEDDS-IV. In contrast, previous studies in dogs suggest that danazol BA is less dependent on first pass metabolism and more sensitive to changes in formulation processing. In vitro digestion models based on likely rat GI conditions suggest less drug precipitation on formulation digestion when compared to equivalent dog models, consistent with the increases in in vivo exposure (fraction absorbed) seen here in ABT-pretreated rats.
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Abstract The impact of gastrointestinal (GI) processing and first pass metabolism on danazol oral bioavailability (BA) was evaluated after administration of self-emulsifying drug delivery systems (SEDDS) in the rat. Danazol absolute BA was determined following oral and intraduodenal (ID) administration of LFCS class IIIA medium chain (MC) formulations at high (SEDDSH-III) and low (SEDDSL-III) drug loading and a lipid free LFCS class IV formulation (SEDDS-IV). Experiments were conducted in the presence and absence of ABT (1-aminobenzotriazole) to evaluate the effect of first pass metabolism. A series of modified in vitro lipolysis tests were developed to better understand the in vivo processing of SEDDS in the rat. Danazol BA was low (45 after oral administration of SEDDS-III or SEDDS-IV. In contrast, previous studies in dogs suggest that danazol BA is less dependent on first pass metabolism and more sensitive to changes in formulation processing. In vitro digestion models based on likely rat GI conditions suggest less drug precipitation on formulation digestion when compared to equivalent dog models, consistent with the increases in in vivo exposure (fraction absorbed) seen here in ABT-pretreated rats. | Original language | English | |---|---| | Pages (from-to) | 4069 - 4083 | | Number of pages | 15 | | Journal | Molecular Pharmaceutics | | Volume | 11 | | Issue number | 11 | | DOIs | | | Publication status | Published - 2014 | Cite this - APA - Author - BIBTEX - Harvard - Standard - RIS - Vancouver

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