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Effect of CYP3A5 and ABCB1 Gene Polymorphisms on Tacrolimus Blood Concentration in Renal Transplant Recipients by Engin Yildirim, Garip Şahin, Zuhal Kaltuş, Ertugrul Çolak

Background: Tacrolimus (Tac) is a calcineurin inhibitor (CNI). Its therapeutic range is narrow and pharmacokinetic properties vary among patients. CYP3A5 and MDR1 single-nucleotide polymorphisms (SNPs) are the most effective polymorphisms that play an significant role in the pharmacokinetics of Tac.
Methods: We investigated the influence of CYP3A5 (A6986G) and MDR1 (C3435T) gene polymorphisms on Tac trough concentration (C0), dose requirements (mg/kg), and dose-adjusted concentrations (ng/mL per mg/kg/d). CYP3A5 [*1/*1 (expresser), *1/*3 (expresser); *3/*3 (non-expresser)] and MDR1 (CC, CT, TT) gene polymorphisms were determined by allele-specific polymerase chain reaction in 67 adult Turkish renal transplant patients. The Tac dose (mg/kg/d) and C0 of each patient was acquired from the patient’s file and dose-adjusted concentrations (ng/mL per mg/kg/d) were calculated at the 1st, 3rd, 6th, and 12th months after transplantation. The correlated serum hematocrit, platelet, urea, creatinine, and albumin were also determined.
Results: The CYP3A5*1/*3 and CYP3A5*3/*3 allelic frequencies were 5.97% and 94.03%, respectively. There were no patients with the CYP3A5*1/*1 genotype.
Tac dose was significantly lower in *3/*3 genotype than in *1/*1 genotype (3rd and 6th months: p ≤ 0.001; 12th month: p ≤ 0.05). Dose-adjusted Tac concentration was statistically higher in the *3/*3 genotype than in *1/*1 genotype at the 3rd and 6th months (p ≤ 0.05). The allelic frequencies of MDR1 CC, CT, and TT were 26.87%, 49.25%, and 23.88%, respectively. No statistically significant differences were detected between MDR1 genotypes and in all analyzed laboratory parameters.
Conclusions: CYP3A5 but not MDR1 genetic polymorphisms affected the Tac pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods can be used for selecting the initial dose to individualize immunosuppressive therapy.

DOI: 10.7754/Clin.Lab.2019.190343