Role of P-glycoprotein in the distribution of the HIV protease inhibitor atazanavir in the brain and male genital tract
- PMID: 24379203
- PMCID: PMC3957845
- DOI: 10.1128/AAC.02031-13
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.
Figures
Similar articles
-
Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients.J Antimicrob Chemother. 2006 Nov;58(5):1009-16. doi: 10.1093/jac/dkl379. Epub 2006 Sep 19. J Antimicrob Chemother. 2006. PMID: 16984898
-
Comparison of ABC transporter modulation by atazanavir in lymphocytes and human brain endothelial cells: ABC transporters are involved in the atazanavir-limited passage across an in vitro human model of the blood-brain barrier.AIDS Res Hum Retroviruses. 2008 Sep;24(9):1147-54. doi: 10.1089/aid.2007.0022. AIDS Res Hum Retroviruses. 2008. PMID: 18729774
-
Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir.Clin Pharmacokinet. 2005;44(10):1035-50. doi: 10.2165/00003088-200544100-00003. Clin Pharmacokinet. 2005. PMID: 16176117 Review.
-
Tenofovir comedication does not impair the steady-state pharmacokinetics of ritonavir-boosted atazanavir in HIV-1-infected adults.Eur J Clin Pharmacol. 2007 Oct;63(10):935-40. doi: 10.1007/s00228-007-0344-y. Epub 2007 Jul 31. Eur J Clin Pharmacol. 2007. PMID: 17665183 Clinical Trial.
-
Atazanavir/ritonavir: a review of its use in HIV therapy.Drugs Today (Barc). 2008 Feb;44(2):103-32. doi: 10.1358/dot.2008.44.2.1137107. Drugs Today (Barc). 2008. PMID: 18389089 Review.
Cited by
-
Intranasal Administration of Dolutegravir-Loaded Nanoemulsion-Based In Situ Gel for Enhanced Bioavailability and Direct Brain Targeting.Gels. 2023 Feb 3;9(2):130. doi: 10.3390/gels9020130. Gels. 2023. PMID: 36826300 Free PMC article.
-
Drug transport across the blood-testis barrier.Am J Transl Res. 2022 Sep 15;14(9):6412-6423. eCollection 2022. Am J Transl Res. 2022. PMID: 36247247 Free PMC article. Review.
-
Nanoparticle delivery system, highly active antiretroviral therapy, and testicular morphology: The role of stereology.Pharmacol Res Perspect. 2021 May;9(3):e00776. doi: 10.1002/prp2.776. Pharmacol Res Perspect. 2021. PMID: 34107163 Free PMC article. Review.
-
Enhanced Solubility and Bioavailability of Dolutegravir by Solid Dispersion Method: In Vitro and In Vivo Evaluation-a Potential Approach for HIV Therapy.AAPS PharmSciTech. 2021 Apr 9;22(3):127. doi: 10.1208/s12249-021-01995-y. AAPS PharmSciTech. 2021. PMID: 33835317
-
Opioid Use Disorders in People Living with HIV/AIDS: A Review of Implications for Patient Outcomes, Drug Interactions, and Neurocognitive Disorders.Pharmacy (Basel). 2020 Sep 11;8(3):168. doi: 10.3390/pharmacy8030168. Pharmacy (Basel). 2020. PMID: 32932786 Free PMC article.
References
-
- Panel on Antiretroviral Guidelines for Adults and Adolescents 2013. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. February 2012. U.S. Department of Health and Human Services, Washington, DC: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf
-
- Stebbing J, Bower M, Mandalia S, Nelson M, Gazzard B. 2006. Highly active anti-retroviral therapy (HAART)-induced maintenance of adaptive but not innate immune parameters is associated with protection from HIV-induced mortality. Clin. Exp. Immunol. 145:271–276. 10.1111/j.1365-2249.2006.03147.x - DOI - PMC - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous