Role of Drug Efflux and Uptake Transporters in Atazanavir Intestinal Permeability and Drug-Drug Interactions

Abstract

Drug transporters such as P-glycoprotein and OATPs regulate intestinal permeability of atazanavir and may contribute to its poor oral bioavailability and drug-drug interactions with other protease inhibitors and TDF.

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

“…Since atazanavir is a known substrate of P-gp, a weak substrate of Mrp1, and an inhibitor of BCRP (23,(29)(30)(31), we performed immunoblot analysis to examine the protein expression of these transporters in whole-brain tissue lysates and isolated seminiferous tubules from both WT and TKO (Mdr1a Ϫ/Ϫ , Mdr1b Ϫ/Ϫ , and Abcg2 Ϫ/Ϫ ) mice. We detected robust bands for P-gp (ϳ170 kDa), Bcrp (ϳ72 kDa), and Mrp1 (ϳ190 kDa) in lysates of seminiferous tubules and whole-brain tissue isolated from WT mice.…”

“…These transporters have been recognized to play an important role in protecting the brain and the testes from xenobiotic exposure (19)(20)(21). Our group and others have previously demonstrated, using several cell culture systems of the BBB, the BTB, and the gastrointestinal tract, as well as ABC transporter-overexpressing cell culture models, that atazanavir is a substrate of P-gp, a much weaker substrate of MRP1, and an inhibitor of BCRP (21)(22)(23).…”

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

“…P-gp has been demonstrated to transport ATV [45,46]. The polymorphism ABCB1-3435C>T has been associated with variations in ATV plasma levels regardless the dosage.…”

“…Other transport proteins such as MRPs seem to play a minor role in ATV efflux from cells whereas organic anion transporter 1B1 (OATP1B1), encoded by SLCO1B1, is involved in the ATV uptake inside the cells [46,52]. Studies focus on polymorphisms at these genes could be of great interest.…”

“…One of the most important ones is the Pregnane X Receptor (PXR) encoded by the NR1I2 gene. PXR regulates the expression of CYP3A4, ABCB1 (P-gp) and SLCO1B1 (OATP1B1) and consequently, genetic variations in this receptor may affect the antiretroviral pharmacokinetics [46]. The most studied polymorphism at NR1I2 is the 63396C>T, which has been associated with an increased activity of CYP3A4, leading to variations in ATV exposure.…”