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  • Title: Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients.
    Author: Qiu XY, Jiao Z, Zhang M, Zhong LJ, Liang HQ, Ma CL, Zhang L, Zhong MK.
    Journal: Eur J Clin Pharmacol; 2008 Nov; 64(11):1069-84. PubMed ID: 18636247.
    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 (C(0) and C(2), 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 C(2), 19.3% (P = 0.008) during days 8-15, 35.2% (P = 0.008) during days 16-30, and for C(0), 39.7% (P = 0.012) during days 16-30. The dose-adjusted C(0) was higher in patients with MDR1 1236CC compared with those with 1236TT in the first month postoperation. The dose-adjusted C(0) 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 C(0) 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 C(2.) 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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