Association of MDR1, CYP3A418B, and CYP3A53 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients

• Published in: European journal of clinical pharmacology Vol. 64; no. 11; pp. 1069 - 1084
• Main Authors: Qiu, Xiao-yan, Jiao, Zheng, Zhang, Ming, Zhong, Long-jin, Liang, Hui-qi, Ma, Chun-lai, Zhang, Liang, Zhong, Ming-kang
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.11.2008; Springer; Springer Nature B.V
• Subjects: Adult; Asian people; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cyclosporine - pharmacokinetics; Cytochrome P-450 CYP3A - genetics; Dose-Response Relationship, Drug; Female; Genotype & phenotype; Graft Rejection - epidemiology; Haplotypes; Humans; Immunosuppressive Agents - pharmacokinetics; Kidney Transplantation; Kidneys; Male; Medical sciences; Middle Aged; Pharmacogenetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Polymorphism; Polymorphism, Single Nucleotide; Prescription drugs; Retrospective Studies; Transplants & implants; Asia; China; CYP3A418B; Renal transplantation; MDR1; Cyclosporine; CYP3A53; Human; Calcineurin inhibitor; Genetic variability; Enzyme; Isozyme; Cytochrome P450; Genotype; Recipient; Kidney; Urinary system; Surgery; MDR-1 gene; Chinese; Ciclosporin; Immunosuppressive agent; Pharmacokinetics; Polymorphism; Kidney transplantation
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-008-0520-8

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.