Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population

Organ Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation 02/2012; 10(1):24-9. DOI: 10.6002/ect.2011.0093
Source: PubMed

ABSTRACT Tacrolimus is widely used as an immunosuppressive drug in liver transplant recipients with a narrow therapeutic range and variable individualized pharmacokinetics. Tacrolimus is a substrate of cytochrome P-450 3A enzyme and the drug transporter, P-glycoprotein.
We determined the genotypic frequencies of cytochrome P-4503A5 (rs776746), and ABCB1 (rs1045642), single nucleotide polymorphisms in a population of 100 Iranian liver transplant patients, and investigated the influence of the above-mentioned single nucleotide polymorphisms on tacrolimus concentrations. At 7 and 30 days after transplant, tacrolimus dosages (mg/kg/d), trough blood levels (T0), and dose-adjusted concentrations (concentration/dosage ratio) were determined. Polymerase chain reaction, followed by restriction fragment length polymorphism analysis, was used for genotyping cytochrome P-4503A5*3 [6986A>G] as well as ABCB1 [3435C>T].
Ninety-five percent of the population showed a cytochrome P-4503A5*3/*3 genotype. ABCB13435TT genotype was observed in 33 cases (33%); whereas 51 cases (51%) carried 3435CT, and 16 cases (16%) carried 3435CC. With regard to the ABCB1 and cytochrome P-4503A5, they showed no influence on tacrolimus dosing requirements at 1 week or 1 month after transplant. No association of any genetic variant with the acute rejection rate was found.
Finally, as the liver donor genotype influences tacrolimus pharmacokinetics with regard to expression of cytochrome P-4503A5, far more than the genotype of the recipient; therefore, it should be considered before recommending any personal immunosuppressive treatment based on pharmacogenetics.

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    ABSTRACT: Studies of liver transplant (LT) patients, mainly in Asians, have evaluated the influence of the CYP3A5*1 allele and P-glycoprotein gene ABCB1 on tacrolimus pharmacokinetics or BPAR (biopsy-proven acute rejection) incidence, with no conclusive results. To investigate these issues,98 Caucasian Spanish LT patients with tacrolimus, mycophenolate mofetil and steroids and 88 cadaveric donors were genotyped for the SNPs CYP3A5 6986G > A, ABCB1 1236C > T, ABCB1 2677G > A/T and ABCB1 3435C > T;. On day 7 post-LT, patients with a native CYP3A5*1 allele had significantly lower tacrolimus trough concentrations C0 (P = 0.03) and dose-adjusted concentrations C0 /D (P = 0.02) than CYP3A5 *3/*3 homozygotes. 3 months post-LT, patients carrying a liver with CYP3A5*1 had significantly lower C0 /D (P = 0.03) and took significantly higher tacrolimus doses (P = 0.03) than the corresponding *3/*3 homozygotes. ABCB1 SNPs showed no significant association with tacrolimus variables. The 3-month incidence of BPAR was 10.2%, with no statistically significant differences related to CYP3A5 (14.3% in expresser vs 9.5% in non-expresser) or ABCB1 genotype of either patient or donor. We conclude that in Caucasian Spanish LT patients, a native or graft-borne CYP3A5*1 allele tends to lower tacrolimus concentrations and increase dosage needs, but has no significant impact on the incidence of BPAR.
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    ABSTRACT: The effect of ABCB1 C3435T SNP on the pharmacokinetics of immunosuppressive drug tacrolimus in different studies was conflicting. So meta-analysis was employed to study the correlation of ABCB1 C3435T SNP and the pharmacokinetics of tacrolimus at different post-transplantation time. Several studies about ABCB1 C3435T polymorphism and the pharmacokinetics of tacrolimus were collected through the search on PubMed and the Cochrane Library. After the extraction of pharmacokinetics parameters from these studies, meta-analysis was performed on the software STATA version11.0. A total of 9 studies were adopted including 558 liver transplant recipients. For the dose of tacrolimus, the subjects with wild-type CC had a significantly higher tacrolimus dose than homozygous mutated genotype TT within 1week (WMD=0.01 (0.00, 0.02), P=0.014) and the similar result in recipients with heterozygous CT compared with TT after transplantation for 1month (WMD=0.01 (0.00, 0.02), P=0.002). For the tacrolimus concentration/dose ratio, subjects with CT had higher C/D ratio than those with CC and TT in different post-transplantation time. The subgroup analysis based on different ethnic population was also carried out. Donors' genotypes were also considered in this meta-analysis. Through this meta-analysis for the including studies about the pharmacokinetics of tacrolimus and ABCB1 C3435T SNP, several significant associations were obtained. Particularly, the Caucasians showed more significant associations between the C/D ratio and ABCB1 C3435T polymorphism, however, the correlations were not steady in different post-transplantation time.
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    ABSTRACT: Many studies have reported reduced tacrolimus dose-adjusted exposure in individuals expressing the CYP3A5*1 allele. A meta-analyses of the current data may help characterize the extent of impact this polymorphism has on tacrolimus pharmacokinetics in adult liver transplant recipients and whether donor or recipient genotype is the most influential factor. Structured searches, of studies that evaluated the association between CYP3A5*1 allele and tacrolimus pharmacokinetics in adult liver transplant recipients, were conducted using Embase and Medline. A meta-analysis comparing tacrolimus daily dose, trough concentrations (C0), and dose-adjusted trough concentrations (C0/dose) across the donor and recipient genotype pairs was conducted using a random effects model. Eight studies, involving a total of 694 adult liver transplant recipients, were included. Dose-adjusted tacrolimus trough concentrations were significantly lower in those in whom the donor or recipient expressed a *1 allele compared with those in whom neither the donor nor recipient expressed this allele at 7 days and 2, 3, 6, and 12 months after transplant [standardized mean differences between expressers and nonexpressers of -1.98, -2.12, -2.39, -3.68, and -3.26 (ng/mL)/(mg·kg·d), respectively]. Results of the meta-analysis demonstrated that, in adult liver transplant patients, CYP3A5 expression in either the donor or recipient resulted in a need for a higher mean tacrolimus daily dose to achieve the target drug exposure. In the immediate posttransplant period, recipient expression of a CYP3A5*1 allele seemed to have the greatest influence on tacrolimus pharmacokinetics with donor expression of a CYP3A5*1 allelle possibly becoming more important with increasing time after transplant.
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May 29, 2014