Effects of a P-glycoprotein inhibitor on brain and plasma concentrations of anti-human immunodeficiency virus drugs administered in combination in rats.
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 and N-(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 (approximately 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.
Savolainen
Jouko
J
Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
Edwards
Jeffrey E
JE
Morgan
Michael E
ME
McNamara
Patrick J
PJ
Anderson
Bradley D
BD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D019888:Nelfinavir / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000493:pharmacokinetics*; D011684:Purine Nucleosides / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines
C096959:6-chloro-9-(2,3-dideoxyribofuranosyl)-9H-purine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; D011355:Prodrugs; D011684:Purine Nucleosides; D044005:Tetrahydroisoquinolines; D019888:Nelfinavir; C083501:Elacridar