PT  - JOURNAL ARTICLE
AU  - Carla B. Washington
AU  - Hugh R. Wiltshire
AU  - Martha Man
AU  - Tina Moy
AU  - Steve R. Harris
AU  - Eric Worth
AU  - Paul Weigl
AU  - Zhenmin Liang
AU  - David Hall
AU  - Lorraine Marriott
AU  - Terrence F. Blaschke
TI  - The Disposition of Saquinavir in Normal and P-glycoprotein Deficient Mice, Rats, and in Cultured Cells
DP  - 2000 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1058--1062
VI  - 28
IP  - 9
4099  - http://dmd.aspetjournals.org/content/28/9/1058.short
4100  - http://dmd.aspetjournals.org/content/28/9/1058.full
SO  - Drug Metab Dispos2000 Sep 01; 28
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics