Influence Of CYP3A5 Genetic Polymorphisms Research Articles

Effect of CYP3A5 polymorphism on the pharmacokinetics of tacrolimus and acute rejection in renal transplant recipients: experience at a single centre.

As a substrate of cytochrome P450 (CYP) 3A5, tacrolimus is characterised by a narrow therapeutic index and large inter-individual variability. Our objective was to determine the influence of CYP3A5 genetic polymorphisms on tacrolimus pharmacokinetics and acute rejection in Chinese renal transplant recipients. Thirty-five renal recipients treated with tacrolimus in our centre were genotyped for CYP3A5 single nucleotide polymorphisms, CYP3A5*1 (6986A) and CYP3A5*3 (6986G). These patients were divided into the following three groups: CYP3A5*1*1 homozygous carriers, CYP3A5*3*3 homozygous carriers and CYP3A5*1*3 heterozygous carriers. Doses administered at 1 week and at 1, 6 and 12 months posttransplantation were recorded. Whole blood concentration was measured using the enzyme-multiplied immunoassay technique. Biopsy-proven acute rejection episodes (BPAR) reported during the first year after transplant were obtained retrospectively. The concentration/dose ratios of CYP3A5*3 homozygous carriers at 1 week and at 1, 6 and 12 months were significantly higher than the ratios among CYP3A5*1 carriers (CYP3A5*1*1 and CYP3A5*1*3, p < 0.05). BPAR occurred in four patients during the first month after transplant, three of whom were CYP3A5*1 carriers. CYP3A5 genetic polymorphism is associated with the concentration/dose ratio of tacrolimus in Chinese renal recipients. Patients with CYP3A5*1*1 genotypes require higher doses of tacrolimus to achieve the target concentration and may be at risk of acute rejection soon after transplant because of inadequate immunosuppression. Screening for this polymorphism could be helpful in choosing the suitable calcineurin inhibitors and determining the suitable initial dose.

Tacrolimus Dose Requirement in Pediatric Liver Transplantation: Influence of CYP3A5 Gene Polymorphism

Little information is available regarding the influence of CYP3A5 genetic polymorphisms on tacrolimus dose requirement in pediatric liver transplantation. We performed a retrospective study among 179 pediatric liver recipients grafted between 2002 and 2009 in order to determine the influence of donor CYP3A5 genotype along with clinical variables on tacrolimus daily dose requirement during the first weeks following transplantation. Mean stable tacrolimus daily dose requirement was higher among children who received a liver expressing CYP3A5 (carrying the CYPA3A5*1 allele) compared with those with a liver that did not express CYP3A5 (CYP3A5*3/*3 genotype): 0.29 ± 0.20 vs 0.18 ± 0.13 mg.kg(-1).d(-1), p = 0.005, respectively. A younger recipient age and fluconazole prescription were also significantly associated with tacrolimus daily dose requirement. Time to reach stable tacrolimus therapeutic trough concentrations was prolonged among patients with a CYP3A5-expressing graft (26 vs 21 days, p = 0.04). Donor CYP3A5 genotype partially explains tacrolimus dose requirement. Original submitted 30 January 2013; Revision submitted 2 May 2013.

Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients

To investigate whether the CYP3A5*3 polymorphism would affect cyclosporine A (CsA) metabolism in Chinese renal transplant patients. The CYP3A5*3 genotype was determined in Chinese renal transplant recipients using polymerase chain reaction and amplification of specific alleles (PCR-ASA). The concentrations of CsA and metabolites were separately measured by fluorescence polarization immunoassay and dose-adjusted trough concentrations and metabolic ratio (MR) values were calculated. The trough concentrations adjusted with the dose was significantly higher in the wild allele carriers compared to both the homozygous (*3*3) and heterozygous variants (*1*3). However, no significant difference was found for the dose-adjusted metabolite concentrations. The MR values for the 3 genotype groups were as follows: 0.92+/-0.62 for CYP3A5*3/ *3 (n=14), 0.99+/-0.51 for CYP3A5*1/*3 (n=15), and 1.45+/-0.62 for CYP3A5*1/*1 (n=9), respectively. Post hoc comparisons showed that only the MR values between the CYP3A5*3/*3 group and the CYP3A5*1/*1 group were significantly different. The CYP3A5*3 polymorphism exerted little effect on cyclosporine metabolism. The MR may be a more accurate indicator for therapeutic drug monitoring, considering its integrated information on body exposure of both parent drugs and metabolites.

Identification of influence of CYP3A5 genetic polymorphism in tacrolimus pharmacokinetics assessed from routine TDM data using population pharmacokinetic approach

Clinical Pharmacology &amp; Therapeutics (2003) 73, P20–P20; doi: