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

Jennifer J. Kiser, Christina L. Aquilante, Peter L. Anderson, Tracy M. King, Monica L. Carten, Courtney V. Fletcher

Research output: Contribution to journalArticlepeer-review

139 Scopus citations


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 cells (range: 16.3 to 212 fmol/10 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 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.

Original languageEnglish (US)
Pages (from-to)298-303
Number of pages6
JournalJournal of Acquired Immune Deficiency Syndromes
Issue number3
StatePublished - Mar 2008


  • Human organic anion transporter 1
  • Intracellular tenofovir
  • Multidrug resistance protein 2
  • Multidrug resistance protein 4
  • Pharmacokinetics
  • Tenofovir diphosphate

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)


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