BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: This study provides direction for future investigations to elucidate the contribution of clinical characteristics and drug transporter genotype to TFV-DP safety and efficacy.
BACKGROUND: 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. OBJECTIVE: We characterized intracellular tenofovir diphosphate (TFV-DP) concentrations in HIV-infectedpatients (n = 30), and investigated associations between TFV-DP concentrations and polymorphisms in the drug transporter genes SLC22A6, ABCC2, and ABCC4. METHODS: Subjects were genotyped for 6 single-nucleotide polymorphisms: 2 in SLC22A6 (encodes influx transporter, humanorganic 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. RESULTS: 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). CONCLUSION: This study provides direction for future investigations to elucidate the contribution of clinical characteristics and drug transporter genotype to TFV-DP safety and efficacy.
Authors: Cecile D Lahiri; Sijia Tao; Yong Jiang; Anandi N Sheth; Edward P Acosta; Vincent C Marconi; Wendy S Armstrong; Raymond F Schinazi; Aswani Vunnava; Sara Sanford; Ighovwerha Ofotokun Journal: AIDS Date: 2015-06-01 Impact factor: 4.177
Authors: Amber Dahlin; Matthias Wittwer; Melanie de la Cruz; Jonathan M Woo; Rujuta Bam; Valeska Scharen-Guivel; John Flaherty; Adrian S Ray; Tomas Cihlar; Samir K Gupta; Kathleen M Giacomini Journal: Pharmacogenet Genomics Date: 2015-02 Impact factor: 2.089