RT Journal Article
SR Electronic
T1 A Pharmacokinetic Model for Evaluating the Impact of Hepatic and Intestinal First-Pass Loss of Saquinavir in the Rat
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 294
OP 301
DO 10.1124/dmd.110.034488
VO 39
IS 2
A1 R. Lledó-García
A1 A. Nácher
A1 V. G. Casabó
A1 M. Merino-Sanjuán
YR 2011
UL http://dmd.aspetjournals.org/content/39/2/294.abstract
AB The aim of this study was to quantify the intestinal and hepatic first-pass loss of saquinavir and to assess the effect of coadministration of ritonavir on this first-pass loss. Single doses of 12, 24, and 48 mg of saquinavir and a dose of 24 mg of saquinavir/6 mg of ritonavir were orally, intravenously, or intraperitoneally administered to 94 rats. Ten groups of animals were studied. A semiphysiological pharmacokinetic model incorporating a population pharmacokinetic analysis [nonlinear mixed-effects model (NONMEM)] was developed to analyze plasma concentration-time profiles after administration via each of the three above-mentioned routes. This model confirmed that saturable metabolism in hepatocytes and enterocytes and dose-dependent precipitation in the peritoneal cavity after intraperitoneal administration characterize the pharmacokinetics of SQV. It also demonstrated that low oral bioavailability of saquinavir is due mainly to intestinal rather than to hepatic first-pass metabolism. In addition, it was shown that ritonavir diminished saquinavir clearance through competitive inhibition. The present report presents a new pharmacokinetic model applied in rats to evaluate the impact of hepatic and intestinal first-pass loss on oral bioavailability.