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
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
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