Received for publication July 13, 2007.
Revised January 17, 2008.
Accepted for publication February 5, 2008.

Differential Roles of Pgp, Mrp2 and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Abstract

The objective of this investigation was to differentiate the roles of Pgp, Mrp2 and CYP3A on saquinavir (SQV) oral absorption. Using single-pass jejunal perfusion (in situ) and portal vein-cannulated rats (in vivo), SQV absorption was studied under chemical inhibition of Pgp (GF120918), Mrp2 (MK571) or/and CYP3A (midazolam). Plasma concentrations of SQV and related metabolites were analyzed by LC-MS/MS. When dosed alone, SQV absorption was extremely low both in situ (Fa = 0.07%) and in vivo (Cmax = 0.068 µg/ml, AUC = 6.8 µg•min/ml). Co-administration of GF120918 boosted SQV absorption for more than 20 fold with decreased variation in AUCs (CV% = 30% vs. 100%). In contrast, co-administration of MK571 or midazolam increased the SQV absorption only 2-3 fold without improving the variation of AUCs. SQV oral absorption was not further improved when dosed with GF120918 and midazolam or GF120918 and MK571. The current results provide, for the first time, direct and explicit evidence that SQV's low oral absorption is controlled by a secretory transporter, Pgp, and not by limited passive diffusion due to its poor physicochemical properties. Pgp mediated transport is also responsible for the highly variable oral bioavailability of SQV. In contrast, intestinal Mrp2 and intestinal CYP3A appear to play minor roles in SQV oral bioavailability. Given the differential and complex roles of Pgp and CYP3A in SQV oral absorption, the optimization of AIDS boosting regimens requires careful consideration in order to avoid therapy limiting drug-drug transporter and enzyme interactions.

Key words: bioavailability, cytochrome P450, intestinal transport, oral absorption, p-glycoprotein

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