The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice

✍ Scribed by Noha N. Salama; Edward J. Kelly; Tot Bui; Rodney J.Y. Ho

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 152 KB
• Volume: 94
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.20344

✦ Synopsis

Insufficient concentrations of protease inhibitors such as nelfinavir may reduce the effectiveness of HIV dementia treatment. The efflux transporter mdr1 product P-glycoprotein (P-gp) has been demonstrated to play a role in limiting nelfinavir brain levels. The goal of this study was to compare the effect of GF120918 (10 mg/kg, IV), a P-gp inhibitor, on intravenous nelfinavir (10 mg/kg) in vivo disposition and tissue penetration in P-gp-competent mdr1a/1b (þ/þ) mice versus P-gp double knockout mdr1a/1b (À/À) mice. Intravenous administration with the P-gp inhibitor GF120918 to mdr1a/1b (þ/þ) mice increased nelfinavir concentrations over a range of 2.3-to 27-fold, whereas nelfinavir distribution in mdr1a/1b (À/À) mice was 2-to 16-fold higher than that in their wild counterparts. Nelfinavir levels after GF120918 coadministration were higher in the heart, liver, and kidneys than those detected with mdr1a/1b knockout mice. In contrast, mdr1a/1b knockout mice exhibited higher nelfinavir levels in the brain (16.1-fold vs. 8.9fold increase) and spleen (4.1-fold vs. 2.3-fold increase) compared to pharmacological inhibition with GF120918 in wild mice. Most notably, GF120918 provided tissue-specific effects in mdr1a/1b knockout mice with enhanced (p < 0.05) drug accumulation in the brain ($21-fold) and heart (3.3-fold). Our results suggest mdr1a/1b-independant mechanisms may also contribute to nelfinavir tissue distribution in mice. ß 2005 Wiley-