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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Differentiation of Gut and Hepatic First Pass Metabolism and Secretion of Saquinavir in Ported Rabbits

Department of Pharmaceutics, School of Pharmacy, Rutgers–The State University of New Jersey, Piscataway, New Jersey (P.J.S., J.R.K., H.H.U.); Mechanism and Extrapolation Technologies, Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (J.R.K.); and Department of Surgery, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey (B.A.P.)

The current study was performed in intestinal and vascular access ported rabbits to quantify and differentiate the components of intestinal and hepatic first pass extraction (i.e., metabolism and secretion) of saquinavir (SQV) mediated by P-glycoprotein (P-gp) and CYP3A. SQV was administered i.v. (1–5 mg/kg) or into the upper small intestine (USI) (5 mg/kg). The roles of intestinal and hepatic secretion by means of P-gp and/or metabolism by CYP3A on the first pass gastrointestinal extraction of SQV were differentiated by using N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (a P-gp inhibitor), midazolam (an inhibitor of CYP3A), or cyclosporine A (an inhibitor of P-gp and CYP3A). The bioavailability (BA) of SQV after USI dosing was 4%. In the presence of CYP3A and P-gp inhibitors, the BA of SQV increased 2- to 11-fold. Based on a relatively unchanged C_max but prolonged T_max and t_1/2, P-gp and CYP3A inhibition appeared to alter SQV disposition (i.e., enhanced oral bioavailability by diminishing SQV elimination and by increasing its net intestinal absorption). In conclusion, the current results substantiate the role of the liver and, for the first time, experimentally establish an important role for the intestine in the net absorption and disposition of SQV. The results also demonstrate that changes in SQV disposition due to the modulation of metabolism and secretion were important and may potentially have considerable implications on multiple drug therapeutic regimens used in the treatment of AIDS.

Address correspondence to: Dr. Patrick J. Sinko, Rutgers University, College of Pharmacy, 160 Frelinghuysen Road, Piscataway, NJ 08854. E-mail: sinko{at}rci.rutgers.edu

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