Role of P-Glycoprotein in the Distribution of the HIV Protease Inhibitor Atazanavir in the Brain and Male Genital Tract

Author:

Robillard Kevin R.,Chan Gary N. Y.,Zhang Guijin,la Porte Charles,Cameron William,Bendayan Reina

Abstract

ABSTRACTThe 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 investigatein vivothe tissue distribution of the HIV protease inhibitor atazanavir in wild-type (WT) mice, P-gp/breast cancer resistance protein (Bcrp)-knockout (Mdr1a−/−,Mdr1b−/−, andAbcg2−/−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 atazanavirCbrain/Cplasma(5.4-fold) andCtestes/Cplasma(4.6-fold) ratios compared to those in WT mice (P< 0.05). Elacridar-treated WT mice showed a significant increase in atazanavirCbrain/Cplasma(12.3-fold) andCtestes/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 atazanavirCbrain/Cplasma(1.8-fold) andCtestes/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.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference54 articles.

1. Panel on Antiretroviral Guidelines for Adults and Adolescents. 2013. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Feb 2012. U.S. Department of Health and Human Services, Washington, DC. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

2. Highly active anti-retroviral therapy (HAART)-induced maintenance of adaptive but not innate immune parameters is associated with protection from HIV-induced mortality;Stebbing;Clin. Exp. Immunol.,2006

3. Current therapy for human immunodeficiency virus infection and acquired immunodeficiency syndrome;Honda;Int. J. Hematol.,2006

4. Attacking the HIV reservoir from the immune and viral perspective;Massanella;Curr. HIV/AIDS Rep.,2013

5. Immune privilege and HIV-1 persistence in the CNS;Persidsky;Immunol. Rev.,2006

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