PT  - JOURNAL ARTICLE
AU  - Jouko Savolainen
AU  - Jeffrey E. Edwards
AU  - Michael E. Morgan
AU  - Patrick J. McNamara
AU  - Bradley D. Anderson
TI  - Effects of a P-Glycoprotein Inhibitor on Brain and Plasma Concentrations of Anti-Human Immunodeficiency Virus Drugs Administered in Combination in Rats
AID  - 10.1124/dmd.30.5.479
DP  - 2002 May 01
TA  - Drug Metabolism and Disposition
PG  - 479--482
VI  - 30
IP  - 5
4099  - http://dmd.aspetjournals.org/content/30/5/479.short
4100  - http://dmd.aspetjournals.org/content/30/5/479.full
SO  - Drug Metab Dispos2002 May 01; 30
AB  - Most of the existing anti-human immunodeficiency virus agents enter the central nervous system (CNS) inefficiently and thus may allow slow viral replication in the brain. This may provide a sanctuary for the virus in the CNS and contribute to the development of acquired immunodeficiency syndrome dementia complex. This study evaluates a prodrug approach to improve the CNS delivery of the reverse transcriptase inhibitor 2′,3′-dideoxyinosine (ddI) in combination with inhibition of P-glycoprotein-mediated efflux to increase the CNS delivery of the protease inhibitor nelfinavir and to determine whether any unanticipated drug interactions occur in this combination therapy. Three rats received either 6-chloro-2′3′-dideoxypurine (6-Cl-ddP), a prodrug of ddI activated by adenosine deaminase, nelfinavir, nelfinavir and 6-Cl-ddP, nelfinavir andN-(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-glycoprotein inhibitor), 6-Cl-ddP and GF120918, or 6-Cl-ddP, nelfinavir, and GF120918. Both 6-Cl-ddP and nelfinavir were administered as i.v. infusions, whereas GF120918 was given as an i.v. bolus 2 h before sampling. Plasma and brain tissue concentrations of 6-Cl-ddP, ddI, and nelfinavir were determined. Neither nelfinavir nor GF120918 was shown to alter the brain/plasma ratios of 6-Cl-ddP or ddI. GF120918, however, increased the plasma concentrations of 6-Cl-ddP and ddI, resulting in increased brain concentrations. GF120918 increased the brain/plasma ratio of nelfinavir significantly (∼100-fold). The brain/plasma ratios of nelfinavir were reduced nearly 2-fold in rats treated with nelfinavir, 6-Cl-ddP, and GF120918 compared with rats receiving only nelfinavir and GF120918, suggesting a modest inhibition of nelfinavir uptake by 6-Cl-ddP. Overall, combined 6-Cl-ddP, nelfinavir, and GF120918 administration enhances the brain/plasma ratios of both ddI and nelfinavir. The American Society for Pharmacology and Experimental Therapeutics