Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients.
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).


CONCLUSIONS
This study provides direction for future investigations to elucidate the contribution of clinical characteristics and drug transporter genotype to TFV-DP safety and efficacy.
Kiser
Jennifer J
JJ
School of Pharmacy, University of Colorado at Denver, Health Sciences Center, Denver, CO, USA.
Aquilante
Christina L
CL
Anderson
Peter L
PL
King
Tracy M
TM
Carten
Monica L
ML
Fletcher
Courtney V
CV
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000328:Adult; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D063065:Organophosphonates / Q000378:metabolism / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D000068698:Tenofovir
D000225:Adenine; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human