The disposition of saquinavir in normal and P-glycoprotein deficient mice,rats, and in cultured cells

Protease inhibitors are very effective in treating patients infected with H IV. However, many drugs in this class penetrate poorly into the central ner vous system (CNS) and may permit this site to be a sanctuary from which res istant virus can emerge. Previous studies have shown that the protease inhi bitor saquinavir (SQV) interacts with the multidrug transport system, P-gly coprotein (P-gp), expressed in epithelial cells in the gut mucosa and at th e blood-brain barrier, and thus might affect both the oral absorption and t he penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue an d plasma was also investigated in rats and in normal and P-gp-deficient mdr 1a(-/-) mice. The distribution ratio of SQV in plasma: brain: cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was en hanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bo lus i.v. injection of [C-14]SQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from md r1a(-/-) mice. Similarly, oral administration of [C-14]SQV (500 mg/kg) resu lted in a 5-fold increase in systemic exposure and a 10-fold increase in br ain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiti ng oral absorption and CNS exposure to this protease inhibitor.