Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients |
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Authors: | Xiao-yan Qiu Zheng Jiao Ming Zhang Long-jin Zhong Hui-qi Liang Chun-lai Ma Liang Zhang Ming-kang Zhong |
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Institution: | (1) Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M. Rd, Shanghai, 200040, People’s Republic of China;(2) School of Pharmacy, Fudan University, Shanghai, People’s Republic of China;(3) Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China |
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Abstract: | Objective 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.
Methods 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.
Results 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.
Conclusion 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. |
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Keywords: | MDR1 CYP3A4*18B CYP3A5*3 Cyclosporine Renal transplantation |
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