title: Role of P-glycoprotein in the distribution of the HIV protease inhibitor atazanavir in the brain and male genital tract.
abstract: The blood-testis barrier and blood-brain barrier are responsible for protecting the male genital tract and central nervous system from xenobiotic exposure. In HIV-infected patients, low concentrations of antiretroviral drugs in cerebrospinal fluid and seminal fluid have been reported. One mechanism that may contribute to reduced concentrations is the expression of ATP-binding cassette drug efflux transporters, such as P-glycoprotein (P-gp). The objective of this study was to investigate in vivo the tissue distribution of the HIV protease inhibitor atazanavir in wild-type (WT) mice, P-gp/breast cancer resistance protein (Bcrp)-knockout (Mdr1a-/-, Mdr1b-/-, and Abcg2-/- triple-knockout [TKO]) mice, and Cyp3a-/- (Cyp) mice. WT mice and Cyp mice were pretreated with a P-gp/Bcrp inhibitor, elacridar (5 mg/kg of body weight), and the HIV protease inhibitor and boosting agent ritonavir (2 mg/kg intravenously [i.v.]), respectively. Atazanavir (10 mg/kg) was administered i.v. Atazanavir concentrations in plasma (Cplasma), brain (Cbrain), and testes (Ctestes) were quantified at various times by liquid chromatography-tandem mass spectrometry. In TKO mice, we demonstrated a significant increase in atazanavir Cbrain/Cplasma (5.4-fold) and Ctestes/Cplasma (4.6-fold) ratios compared to those in WT mice (P<0.05). Elacridar-treated WT mice showed a significant increase in atazanavir Cbrain/Cplasma (12.3-fold) and Ctestes/Cplasma (13.5-fold) ratios compared to those in vehicle-treated WT mice. In Cyp mice pretreated with ritonavir, significant (P<0.05) increases in atazanavir Cbrain/Cplasma (1.8-fold) and Ctestes/Cplasma (9.5-fold) ratios compared to those in vehicle-treated WT mice were observed. These data suggest that drug efflux transporters, i.e., P-gp, are involved in limiting the ability of atazanavir to permeate the rodent brain and genital tract. Since these transporters are known to be expressed in humans, they could contribute to the low cerebrospinal and seminal fluid antiretroviral concentrations reported in the clinic.
authors.affiliation: Graduate Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Robillard
authors.forename: Gary N Y
authors.initials: GN
authors.lastname: Chan
authors.forename: Guijin
authors.initials: G
authors.lastname: Zhang
authors.forename: Charles
authors.initials: C
authors.lastname: la Porte
authors.forename: William
authors.initials: W
authors.lastname: Cameron
authors.forename: Reina
authors.initials: R
authors.lastname: Bendayan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D000069446:Atazanavir Sulfate; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D017320:HIV Protease Inhibitors / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009842:Oligopeptides / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics; D012671:Seminiferous Tubules / Q000737:chemistry / Q000378:metabolism*; D013737:Testis / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000069446:Atazanavir Sulfate; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D019438:Ritonavir; C501412:Abcg2 protein, mouse; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins