Genetic Polymorphisms in Relation to Immunosuppressive Drug Pharmacokinetics in Organ Transplantation: Current Knowledge and Perspectives

M.      Mourad; P.      Wallemacq; J.      Lerut; M.   De   Meyer; J.      Malaise; D.   Chaib   Eddour; O.      Ciccarelli; D.      Lison; V.      Haufroid

Abstract

The primary goal of immunosuppressive treatment after organ transplantation is to optimize its benefit/risk ratio in order to have the best combination of efficacy and tolerability. Tacrolimus (Tc), Sir (SRL), cyclosporine (CsA) and mycophenolic acid based drugs are characterized by a narrow therapeutic index and broad interindividual variability in their pharmacokinetic parameters. Their bioavailability is affected by a range of factors including absorption, distribution, biotransformation and elimination, resulting in considerable disparity in drug safety and efficacy profiles. Therapeutic monitoring is becoming a crucial component of routine practice to maintain time-dependent target concentrations. Recently, special interest in polymorphisms in genes encoding biotransformation enzymes and drug transporters has opened promising new perspectives for the selection of individual dosages. Several single nucleotide polymorphisms (SNP) have been identified in both CYP3A4 and CYP3A5 as well as in UGT genes encoding metabolizing enzymes, and in ABCB1 and ABCC2 genes encoding membranous transporters. A particular SNP within intron 3 of the CYP3A5 gene has been shown to generate production of a truncated protein associated with the CYP3A5*3 allele and expression of the active CYP3A5 enzyme with its CYP3A5*1 allele. The functional significance of this SNP has been confirmed with respect to Tc in the stable phase after kidney, liver, heart and lung transplantation. The same effect is also seen in the early phase after kidney transplantation, even following initial administrations of the drug. The influence of the CYP3A5 SNP in intron 3 is less marked in case of CsA administration, and however, was recently demonstrated for SRL disposition in some circumstances. Findings on the contribution of ABCB1 SNPs to interindividual variability in blood levels of immunosuppressive drugs remain contradictory. Prospective studies are still needed to prove that a genetic approach, in association with therapeutic drug monitoring, may enhance efficacy and safety, both in the short and long term after transplantation.

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