Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients
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- Qiu, X., Jiao, Z., Zhang, M. et al. Eur J Clin Pharmacol (2008) 64: 1069. doi:10.1007/s00228-008-0520-8
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The objective of this study was to retrospectively evaluate the effects of MDR1, CYP3A4*18B, and CYP3A5*3 genetic polymorphisms on cyclosporine A (CsA) pharmacokinetics in Chinese renal transplant patients during the first month after transplantation.
A total of 103 renal transplant recipients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A, and C3435T), CYP3A4*18B, and CYP3A5*3. The predose and 2-h postdose concentrations of CsA (C0 and C2, respectively) were determined by fluorescence polarization immunoassay, and their relationships with corresponding genotypes and haplotypes were investigated.
Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted concentration compared with those with CYP3A4*18B/*18B, as follows: for C2, 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16–30, and for C0, 39.7% (P = 0.012) during days 16–30. The dose-adjusted C0 was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C0 in patients with the CYP3A5*3/*3 genotype was 25.5% and 30.7% higher than those with the wild-type genotype during days 8–15 (P = 0.011) and days 16–30 (P = 0.015), respectively. Haplotype analysis revealed that the dose-adjusted C0 was higher in the first month following surgery in carriers of haplotype MDR1 CAC than in noncarriers. Polymorphisms of MDR1 and CYP3A5*3 did not affect dose-adjusted C2.
The data suggests that the CYP3A4*18B genotype affects CsA pharmacokinetics during the first month following surgery in Chinese renal transplant recipients. Patients with CYP3A4*18B alleles may require higher doses of CsA to reach the target levels. Large prospective studies may be needed to further explore the impact of MDR1 and CYP3A5*3 polymorphisms on CsA pharmacokinetics in renal transplant recipients.