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Clearance and clearance inhibition of the HIV-1 protease inhibitors ritonavir and saquinavir in sandwich-cultured rat hepatocytes and rat microsomes

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Author: Treijtel, N. · Eijkeren, J.C.H.v. · Nijmeijer, S. · Greef de - Sandt, I.C.J. van der · Freidig, A.P.
Institution: TNO Kwaliteit van Leven
Source:Toxicology in Vitro, 1, 23, 185-193
Identifier: 241394
doi: doi:10.1016/j.tiv.2008.11.001
Keywords: Health · Biomedical Research · HIV-protease inhibitors · Metabolism · P-Glycoprotein · Rat hepatocytes · rat liver microsomes · Sandwich-culture · cyclosporin A · drug metabolite · glycoprotein P · ketoconazole · proteinase inhibitor · ritonavir · saquinavir · testosterone derivative · valspodar · verapamil · animal cell · article · cell culture · controlled study · drug clearance · drug excretion · drug metabolism · drug transport · Human immunodeficiency virus 1 · hydroxylation · intrahepatic bile duct · liver cell · liver metabolism · male · microsome · nonhuman · rat · sandwich culture · Animals · Biological Transport, Active · Cell Culture Techniques · Cell Survival · Cells, Cultured · Cyclosporine · Cyclosporins · Dose-Response Relationship, Drug · Hepatocytes · HIV Protease Inhibitors · Ketoconazole · Male · Metabolic Clearance Rate · Microsomes, Liver · Rats · Rats, Wistar · Ritonavir · Saquinavir · Human immunodeficiency virus 1 · Rattus


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.