Adverse Drug Reactions and Pharmacogenomics: Recent Advances

Ana Alfirevic; Munir Pirmohamed


Personalized Medicine. 2008;5(1):11-23. 

In This Article


The short-term benefits of the calcineurin inhibitors cyclosporine and tacrolimus are unquestionable in transplant patients. Long-term use, however, has been associated with nephrotoxicity and cardiovascular disease. The prevalence of renal failure in heart transplant recipients varies in different studies and the incidence of end-stage renal disease requiring dialysis has reached 3.9%.[40] Identification of patients at risk for renal failure and adjustment of therapy has the potential to prevent this complication. Several studies have now shown that renal failure after heart transplantation is associated with TGF-ß polymorphisms.[41,42] Nephrotoxicity after kidney transplantation, however, has been associated with polymorphisms in the ABCB1 gene (encoding the drug transporter P-glycoprotein) of the donor kidney, but not of the recipient.[43] Tacrolimus pharmacokinetics are highly correlated with polymorphic expression of enzymes involved in its metabolism, mainly CYP3A4 and CYP3A5, and modulated by P-glycoprotein.[44] In particular, CYP3A5 genotype seems to be predictive of the tacrolimus dose and nephrotoxicity.[45]

Several antiretroviral drugs have been associated with significant nephrotoxicity in clinical practice.[46] Although tenofovir nephrotoxicity was not detected in premarketing clinical trials, proximal tubular dysfunction and acute tubular necrosis have been reported in retrospective cohort studies and prospective clinical trials.[47] Izzedine et al. recently reported an association between tenofovir-induced proximal tubulopathy and variants in the ABCC2 gene, which encodes multidrug resistance associated protein MRP2.[48] Tenofovir is a substrate for MRP2 providing some biological plausibility that changes in disposition of tenofovir may represent a risk factor for nephrotoxicity. However, this study was undertaken in a small number of patients (13 with tenofovir-induced renal proximal tubulopathy and 17 patients who were tenofovir tolerant) and needs to be replicated in an independent cohort.