The role of drug transporters in the kidney: lessons from tenofovir

Abstract

Tenofovir disoproxil fumarate, the prodrug of nucleotide reverse transcriptase inhibitor tenofovir, shows high efficacy and relatively low toxicity in HIV patients. However, long-term kidney toxicity is now acknowledged as a modest but significant risk for tenofovir-containing regimens, and continuous use of tenofovir in HIV therapy is currently under question by practitioners and researchers. Co-morbidities (hepatitis C, diabetes), low body weight, older age, concomitant administration of potentially nephrotoxic drugs, low CD4 count, and duration of therapy are all risk factors associated with tenofovir-associated tubular dysfunction. Tenofovir is predominantly eliminated via the proximal tubules of the kidney, therefore drug transporters expressed in renal proximal tubule cells are believed to influence tenofovir plasma concentration and toxicity in the kidney. We review here the current evidence that the actions, pharmacogenetics, and drug interactions of drug transporters are relevant factors for tenofovir-associated tubular dysfunction. The use of creatinine and novel biomarkers for kidney damage, and the role that drug transporters play in biomarker disposition, are discussed. The lessons learnt from investigating the role of transporters in tenofovir kidney elimination and toxicity can be utilized for future drug development and clinical management programs.

Keywords: drug transporters; kidney; pharmacokinetics; tenofovir; toxicity.

FIGURE 1

Confirmed and potential transporters involved in active tubular secretion of tenofovir into urine. Tenofovir is removed from the circulating blood and enters the proximal tubule cells by the actions of basolaterally expressed SLC22A6 and, to a lesser extent, SLC22A8. Tenofovir is then removed into the tubular lumen by apically expressed ABCC4. ABCC2 does not transport tenofovir in vitro but pharacogenetics suggests ABCC2 has a role in tenofovir-induced renal toxicity. The orientation of ABCC10 in proximal tubule cells is unknown, but in vitro and pharmacogenetic data suggest that expression may be localized to the apical membrane, facilitating tenofovir secretion.