Print Email Facebook Twitter Clearance and clearance inhibition of the HIV-1 protease inhibitors ritonavir and saquinavir in sandwich-cultured rat hepatocytes and rat microsomes Title Clearance and clearance inhibition of the HIV-1 protease inhibitors ritonavir and saquinavir in sandwich-cultured rat hepatocytes and rat microsomes Author Treijtel, N. Eijkeren, J.C.H.v. Nijmeijer, S. van der Greef de - Sandt, I.C.J. Freidig, A.P. TNO Kwaliteit van Leven Publication year 2009 Abstract The metabolism and active transport of ritonavir and saquinavir were studied using sandwich-cultured rat hepatoyctes and rat liver microsomes. For ritonavir four comparable metabolites were observed in the sandwich-culture and in microsomes. For saquinavir eight metabolites were observed in sandwich-culture and 14 different metabolites in microsomes. Ketoconazole did not affect the metabolism of ritonavir in sandwich-culture or microsomes and slightly inhibited the metabolism of saquinavir in sandwich-culture. This inhibition resulted in a different metabolite profile for saquinavir in microsomes. Ritonavir had a pronounced inhibiting effect on the metabolism of saquinavir and affected the hydroxylation of 6β-testosterone negatively. In the active transport studies, cyclosporin A and PSC833 enhanced the metabolism of ritonavir, suggesting that ritonavir is normally excreted into the bile canaliculi. Verapamil, showed no effect on the metabolism of ritonavir. The intrinsic clearance was estimated at 1.65 and 67.5 μl/min/1 × 106 cells and the hepatic metabolism clearance at 0.017 and 6.83 ml/min/SRW for ritonavir and saquinavir respectively. In conclusion, for saquinavir the metabolism rate and the amount of metabolites produced was higher than for ritonavir. Ritonavir had a strong inhibitory effect on the metabolism of saquinavir and seemed to be excreted into the bile. © 2008 Elsevier Ltd. All rights reserved. Subject HealthBiomedical ResearchHIV-protease inhibitorsMetabolismP-GlycoproteinRat hepatocytesrat liver microsomesSandwich-culturecyclosporin Adrug metaboliteglycoprotein Pketoconazoleproteinase inhibitorritonavirsaquinavirtestosterone derivativevalspodarverapamilanimal cellarticlecell culturecontrolled studydrug clearancedrug excretiondrug metabolismdrug transportHuman immunodeficiency virus 1hydroxylationintrahepatic bile ductliver cellliver metabolismmalemicrosomenonhumanratsandwich cultureAnimalsBiological Transport, ActiveCell Culture TechniquesCell SurvivalCells, CulturedCyclosporineCyclosporinsDose-Response Relationship, DrugHepatocytesHIV Protease InhibitorsKetoconazoleMaleMetabolic Clearance RateMicrosomes, LiverRatsRats, WistarRitonavirSaquinavirHuman immunodeficiency virus 1Rattus To reference this document use: http://resolver.tudelft.nl/uuid:be67a180-ed93-458c-ab25-a3aaaa1d9950 DOI https://doi.org/10.1016/j.tiv.2008.11.001 TNO identifier 241394 ISSN 0887-2333 Source Toxicology in Vitro, 23 (1), 185-193 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.