Hepatobiliary and intestinal elimination of darunavir in an integrated preclinical rat model. (June 2014)

• Record Type: Journal Article
• Authors: Stappaerts, Jef; Fattah, Sarinj; Annaert, Pieter; Augustijns, Patrick
• Is Part Of: Xenobiotica. Volume 44:Number 6(2014:Jun.)
• Page Start: 489
• Page End: 497
• Publication Date: 2014-06
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2013.861541
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. Although valuable <italic>in vitro</italic> models exist to study drug elimination from the systemic circulation, more integrated models may improve mechanistic insight in a biorelevant setting.</p> <p>2. This study aimed to explore (1) intestinal and biliary excretion of the HIV protease inhibitor darunavir and its impact on systemic disposition and (2) to evaluate to what extent findings in an <italic>in situ</italic> excretion model in rat can be captured by individual <italic>in vitro</italic> models.</p> <p>3. Contemporary <italic>in vitro</italic> models were applied to study intestinal and hepatobiliary disposition of darunavir and data were compared with findings in the <italic>in situ</italic> excretion model.</p> <p>4. Both <italic>in situ</italic> and <italic>in vitro</italic> experiments demonstrated significant metabolism of darunavir, which could be strongly inhibited by the P450 inhibitor 1-aminobenzotriazole. Using the P-gp inhibitor zosuquidar, P-gp mediated excretion of darunavir from blood towards gastrointestinal lumen was evidenced and this was confirmed by transport studies in Caco-2 cells. Moreover, involvement of P-gp in the biliary excretion of darunavir was also demonstrated <italic>in situ.</italic></p> <p>5. In general, <italic>in situ</italic> findings corresponded well with <italic>in vitro</italic> data. The <italic>in situ</italic> excretion model offers the possibility to gain mechanistic insight in intestinal and hepatobiliary excretion processes and, at the same time, evaluate their impact on the systemic disposition of a compound.</p> </abstract>