Abstract
The intracellular penetration of darunavir, a second-generation HIV protease inhibitor, is limited by the activity of the efflux P-glycoprotein (ABCB1). ABCB1 expression and/or activity levels can vary between individuals due to genetic polymorphisms including the c.1199G>A, c.1236C>T, c.2677G>T and c.3435C>T variants, which could in part explain why the pharmacokinetics of darunavir are so variable from one individual to another. While a few clinical studies have failed to demonstrate an influence of these polymorphisms on darunavir pharmacokinetics, drug-drug interactions and methodological limitations may have prevented them from revealing the true influence of ABCB1 variants. In this work, we report on the intracellular accumulation of darunavir in recombinant HEK293 cell lines expressing wild-type ABCB1 or one of several variants: ABCB1 1199A, ABCB1 3435T, and ABCB1 1236T/2677T/3435T. We demonstrate that while ABCB1 expression limits intracellular accumulation of darunavir, there is no significant difference in efflux activity between cells expressing wild-type ABCB1 and those that express any of the studied variants.
Highlights
The intracellular penetration of darunavir, a second-generation HIV protease inhibitor, is limited by the activity of the efflux P-glycoprotein (ABCB1)
Abbreviations COB Cobicistat cerebrospinal fluid (CSF) Cerebrospinal fluid DRV Darunavir DRV-d9 Deuterated darunavir EDTA Ethylenediaminetetraacetate fetal bovine serum (FBS) Fetal bovine serum FITC Fluorescein isothiocyanate HEK Human embryonic kidney LC–MS/MS Liquid chromatography coupled with tandem mass spectrometry MAF Minor allele frequency PBS Phosphate buffer saline PK Pharmacokinetic RTV Ritonavir single nucleotide polymorphisms (SNPs) Single nucleotide polymorphism
Calcagno et al studied the paired PK of DRV in plasma and cerebrospinal fluid (CSF) in 41 patients and showed that there was no influence of ABCB1 c.1236C>T, c.2677G>T or c.3435C>T on DRV penetration in the central nervous system, as assessed by the ratio of concentrations between the CSF and p lasma[14]
Summary
The intracellular penetration of darunavir, a second-generation HIV protease inhibitor, is limited by the activity of the efflux P-glycoprotein (ABCB1). ABCB1 expression and/or activity levels can vary between individuals due to genetic polymorphisms including the c.1199G>A, c.1236C>T, c.2677G>T and c.3435C>T variants, which could in part explain why the pharmacokinetics of darunavir are so variable from one individual to another. We demonstrate that while ABCB1 expression limits intracellular accumulation of darunavir, there is no significant difference in efflux activity between cells expressing wild-type ABCB1 and those that express any of the studied variants. ABCB1 controls drug accumulation in lymphocytes, the active site of antiretrovirals, thereby directly limiting the ability of DRV to reach its target It is expressed in other organs, including the blood–brain barrier, meaning it could limit penetration in the central nervous system, which has been described as a sanctuary site for HIV. Even when in vitro associations are found, these do not necessarily translate into in vivo associations probably due to compensatory mechanisms, confounding factors or D DIs10
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