Highlights from the latest articles in pharmacogenomics of solid organ transplantation.

Abstract

2014 Understanding the pharmacogenetics of tacrolimus may help in adequate immunosuppression Evaluation of: Li CJ, Li L, Lin L et al. Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. PLoS ONE 9(1), e86206 (2014). Solid organ transplantation is the treatment of choice for patients with end-stage organ failure. Recent studies have shown a significant improvement in graft survival. This improvement results from the introduction of new immunosuppressive drugs that prevent rejection episodes. The susceptibility to developing adverse events or therapeutic failure varies between patients. An important part of this variability in drug response is thought to be the consequence of interindividual differences in drug metabolism. Some individuals have relatively fast drug clearance, while others exhibit a slower drug elimination rate. Because there is no reliable monitoring of the immunological status of patients receiving immunosuppressive drugs, many attempts have been made to optimize therapeutic drug monitoring by determining the blood concentrations of these drugs. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters has led to the hypothesis that genetic factors may be implicated in the interindividual variability of pharmaco kinetics and pharmacodynamics of immunosuppressive drugs [1]. The role of pharmacogenetics and specific genetic polymorphisms in the choice of treatment is of growing interest. Tacrolimus is a macrolide antibiotic that is widely used to prevent acute rejection after solid organ transplantation. This drug is indicated for the prevention of organ rejection in patients receiving a liver, kidney or heart transplant [2]. Because tacrolimus is metabolized extensively by CYP3A4 and CYP3A5 isoenzymes, polymorphisms in CYP3A4 and CYP3A5 genes have been reported that affect tacrolimus dosing and serum concentrations, and may be helpful in dosing of tacrolimus in kidney transplant recipients [3,4]. Li and colleagues designed a study in the search for genetic determinants of tacrolimus metabolism in Chinese renal transplant recipients [5]. In the retrospective study, the authors evaluated the influence of CYP3A4, CYP3A5, COMT, IL-10 and POR SNPs on concentration/dose ratio (C0/D) and the time required to reach the target blood concentration range during the early phase after transplantation. They found that CYP3A5*3, CYP3A4*1G and CYP3A4 rs4646437 T>C polymorphisms presented a significant association with tacrolimus C0/D at different time points after transplantation. Moreover, the CYP3A5*3 allele and CYP3A4 rs4646437 T>C were strongly associated with tacrolimus pharmacokinetics. IL-10 rs1800871 polymorphism was associated with tacrolimus blood concentration at week 3 after transplantation. None of the COMT and POR variants had a significant association with C0/D. This study confirmed the results of previous investigators indicating an association between CYP3A4 and CYP3A5 polymorphisms and tacrolimus pharmacokinetics. Understanding the pharmacogenetics of tacrolimus may enable individualized therapy, resulting in adequate Highlights from the latest articles in pharmacogenomics of solid organ transplantation