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.
Highlights
Tenofovir, administered as the prodrug tenofovir disoproxil fumarate, is a nucleotide reverse transcriptase inhibitor which is recommended for use in first-line treatment of HIV infection
Evidence is emerging that high concentrations of tenofovir in plasma are associated with development of kidney damage, and it is likely that drug transporters play a role in this association (Barditch-Crovo et al, 2001; Rodriguez-Novoa et al, 2009a) as well as in perturbations of the commonly used biomarker, creatinine (Fernandez-Fernandez et al, 2011)
Tenofovir is predominantly eliminated via the proximal tubules of the kidney, and this review summarizes our current understanding of how kidney transporter polymorphisms and drug interactions may influence tenofovir-associated nephrotoxicity
Summary
Tenofovir, administered as the prodrug tenofovir disoproxil fumarate, is a nucleotide reverse transcriptase inhibitor which is recommended for use in first-line treatment of HIV infection. Long-term kidney toxicity is acknowledged as a modest but significant risk for tenofovir-containing regimens (Cooper et al, 2010) It has been observed in a particular clinic that tenofovir-associated nephrotoxicity is the most common single reason for HIV-related referral to specialist renal services, accounting for more than 20% of consultations (Hall et al, 2011). It is acknowledged that drug transporters play a significant role in the absorption, distribution, metabolism, elimination (ADME), efficacy, and toxicity of numerous drugs. They are detectable in virtually all tissues, the precise orientation and function of many transporters are not fully understood (Bleasby et al, 2006). The lessons learnt from investigating the role of transporters in tenofovir kidney elimination and toxicity can be utilized for future drug www.frontiersin.org
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