Abstract
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.
Footnotes
This research was supported in part by the Ministerio de Ciencia e Innovación, Spain [Project Reference SAF2009-12767].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.034488.
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ABBREVIATIONS:
- SQV
- saquinavir
- RTV
- ritonavir
- NONMEM
- nonlinear mixed-effects model
- IIV
- interindividual variability
- MOFV
- minimum value of objective function
- QMA
- maximum amount of drug that binds to proteins
- FE
- the fraction of dose escaping from the intestine
- Fh
- the fraction escaping from the liver
- Clise
- clearance of intestinal secretion.
- Received May 18, 2010.
- Accepted October 25, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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