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Vol. 28, Issue 9, 1058-1062, September 2000
Division of Clinical Pharmacology, Department of Medicine, Stanford
University School of Medicine, Stanford, California (C.B.W., M.M.,
T.M., T.F.B.); Roche Discovery, Welwyn, England (H.R.W., S.R.H., E.W.);
Hoffman-La Roche, Nutley, New Jersey (P.W., Z.L.); and Quintiles
Scotland Ltd., Edinburg, Scotland (D.H., L.M.)
Protease inhibitors are very effective in treating patients
infected with HIV. However, many drugs in this class penetrate poorly
into the central nervous system (CNS) and may permit this site to be a
sanctuary from which resistant virus can emerge. Previous studies have
shown that the protease inhibitor saquinavir (SQV) interacts with the
multidrug transport system, P-glycoprotein (P-gp), expressed in
epithelial cells in the gut mucosa and at the blood-brain barrier, and
thus might affect both the oral absorption and the 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 and
plasma was also investigated in rats and in normal and P-gp-deficient
mdr1a(
/) mice. The distribution ratio of SQV in
plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats.
The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative)
versus Dx5 cells (P-gp-positive). Bolus i.v. injection of
[14C]SQV (2 and 5 mg/kg) into mdr1a(/) and normal
mice (n = 3 or 4) resulted in 3-fold higher
radioactivity in brains from mdr1a(/) mice. Similarly, oral
administration of [14C]SQV (500 mg/kg) resulted in a
5-fold increase in systemic exposure and a 10-fold increase in brain
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
limiting oral absorption and CNS exposure to this protease inhibitor.
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