Clinical and Genetic Determinants of Intracellular Tenofovir Diphosphate Concentrations in HIV-Infected Patients

Abstract

Nucleos(t)ide reverse transcriptase inhibitors (NRTIs), such as tenofovir, require intracellular phosphorylation for pharmacologic activity. Drug transporters may contribute to the intracellular disposition of NRTIs. We characterized intracellular tenofovir diphosphate (TFV-DP) concentrations in HIV-infected patients (n = 30), and investigated associations between TFV-DP concentrations and polymorphisms in the drug transporter genes SLC22A6, ABCC2, and ABCC4. Subjects were genotyped for 6 single-nucleotide polymorphisms: 2 in SLC22A6 (encodes influx transporter, human organic anion transporter 1), 728G>A and 453G>A; 2 in ABCC2 (encodes efflux transporter, multidrug resistance protein [MRP] 2), -24C>T and 1249G>A; and 2 in ABCC4 (encodes efflux transporter, MRP4), 3463A>G and 4131T>G. The mean TFV-DP was 76.1 fmol/10(6) cells (range: 16.3 to 212 fmol/10(6) cells). Tenofovir apparent oral and renal clearances were significantly predictive of intracellular TFV-DP concentrations. For every 1-L/h decrease in tenofovir renal clearance, there was, on average, an 8% increase in TFV-DP (P = 0.002). We identified a novel relation between ABCC4 3463A>G genotype and TFV-DP. ABCC4 3463G variants had TFV-DP concentrations 35% higher (29 fmol/10(6) cells) than wild type (P = 0.04). This study provides direction for future investigations to elucidate the contribution of clinical characteristics and drug transporter genotype to TFV-DP safety and efficacy.