title: P-glycoprotein-mediated active efflux of the anti-HIV1 nucleoside abacavir limits cellular accumulation and brain distribution.
abstract: P-glycoprotein (P-gp)-mediated efflux at the blood-brain barrier has been implicated in limiting the brain distribution of many anti-HIV1 drugs, primarily protease inhibitors, resulting in suboptimal concentrations in this important sanctuary site. The objective of this study was to characterize the interaction of abacavir with P-gp and determine whether P-gp is an important mechanism in limiting abacavir delivery to the central nervous system (CNS). In vitro and in vivo techniques were employed to characterize this interaction. Abacavir stimulated P-gp ATPase activity at high concentrations. The cellular accumulation of abacavir was significantly decreased by approximately 70% in Madin-Darby canine kidney II (MDCKII)-MDR1 monolayers compared with wild-type cells and was completely restored by the P-gp inhibitors ((R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo(a,e)cyclopropa(c)cycloheptan-6-yl)-alpha-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride) (LY335979) and N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide (GF120918). Directional flux experiments indicated that abacavir had greater permeability in the basolateral-to-apical direction (1.58E-05 cm/s) than in the apical-to-basolateral direction (3.44E-06 cm/s) in MDR1-transfected monolayers. The directionality in net flux was abolished by both LY335979 and GF120918. In vivo brain distribution studies showed that the AUC(plasma) in mdr1a(-/-) CF-1 mutant mice was approximately 2-fold greater than the AUC(plasma) in the wild type, whereas the AUC(brain) in the mutant was 20-fold higher than that in the wild type. Therefore, the CNS drug targeting index, defined as the ratio of AUC brain-to-plasma for mutant over wild type, was greater than 10. These data are the first in vitro and in vivo evidence that a nucleoside reverse transcriptase inhibitor is a P-gp substrate. The remarkable increase in abacavir brain distribution in P-gp-deficient mutant mice over wild-type mice suggests that P-gp may play a significant role in restricting the abacavir distribution to the CNS.
authors: Department of Pharmaceutics, University of Minnesota, 308 Harvard St. SE, Room 9-125, Weaver-Densford Hall, Minneapolis, MN 55455, USA.
authors: Naveed
authors: N
authors: Shaik
authors: Nagdeep
authors: N
authors: Giri
authors: Guoyu
authors: G
authors: Pan
authors: William F
authors: WF
authors: Elmquist
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000166:Acridines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003986:Dibenzocycloheptenes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D015224:Dideoxynucleosides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D014747:Vinblastine / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D015215:Zidovudine / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000099227:Abacavir
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000251:Adenosine Triphosphatases; D019380:Anti-HIV Agents; D003986:Dibenzocycloheptenes; D015224:Dideoxynucleosides; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; D044005:Tetrahydroisoquinolines; D014747:Vinblastine; D015215:Zidovudine; D000099227:Abacavir; C095179:zosuquidar trihydrochloride; C095122:multidrug resistance protein 3; C083501:Elacridar