Investigation of the pharmacokinetic interaction between ritonavir and CMDCK, a new non-nucleoside reverse...

The aim of this study was to investigate the pharmacokinetic interaction between ritonavir (RTV) and an anti-HIV agent 3-cyanomethyl-4-methyl-DCK (CMDCK). CMDCK was administered orally (8 mg/kg) and intravenously (2 mg/kg) to rats in the absence or presence of RTV (1 or 2.5 mg/kg). By comparing the pharmacokinetic parameters between the control and the RTV treated groups, it was found that co-administration with RTV could significantly increase the plasma exposure of CMDCK, through improving the hepatic and intestinal availabilities. The AUCinf of CMDCK was increased by 2.4 or 8.7 times for intravenous or oral route, respectively. The oral bioavailability of CMDCK was increased from 15% of the control group to 45% of the RTV concomitant group (2.5 mg/kg). In the in vitro studies with liver and intestinal microsomes, the K i values of RTV on the CMDCK metabolism were determined and found to be 0.22 and 0.48 µM for human, 0.33 and 1.60 µM for rat, respectively. Caco-2 cells study showed that CMDCK is not a P-glycoprotein (P-gp) substrate and its transepithelial transport is mainly through passive diffusion. The in vitro and in vivo results indicate that RTV could improve the bioavailability of CMDCK by inhibiting CYP3A mediated metabolism in both liver and intestine.