Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Abstract

Abstract. Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C 0 ) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5 For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C 0 levels were significantly lower in patients with one copy of the * 1 allele compared to those homozygous for the * 3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.

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Benefits of minimizing immunosuppressive dosage according to cytochrome P450 3A5 genotype in liver transplant patients: findings from a single-center study

“…Shi et al (2013) studied tacrolimus pharmacokinetics and concluded that patient-specific differences in tacrolimus response could probably be explained by different intestinal CYP3A5 genotypes. A significant difference in tacrolimus daily dose and C/D ratios has also been reported between recipients with the CYP3A5 6986GG allele and those with the CYP3A5 6986AG/AA allele within 6 months of transplantation (Provenzani et al, 2011). A previous study also found that the genetic polymorphism of intestinal CYP3A5 in liver transplant patients was an important factor affecting tacrolimus blood concentration (Uesugi et al, 2006).…”