ABCB1 haplotype influences the sirolimus dose requirements in Chinese renal transplant recipients

摘要

Sirolimus, an immunosuppressive drug used to prevent organ rejection after renal transplantation, has a narrow therapeutic index and a large inter-individual variability of pharmaco-kinetics. The aim of this study was to analyse the dose-normalized trough blood concentrations (C_0/D ratio) of sirolimus in patients with different genotypes and attempt to investigate the possible associations between ABCB1/CYP3A5 genotypes and sirolimus dose requirements in Chinese renal transplant recipients. Blood samples were collected from 85 Chinese renal transplant recipients who were treated with sirolimus for at least 3 months and polymorphisms of the ABCB1 and CYP3A5 were determined by the SNaPShot multiplex assay. The blood concentrations of sirolimus were determined with HPLC. A significant allele-dependent effect was observed between the CYP3A5*3 polymorphism and the C_0/D ratio of sirolimus. The patients bearing at least one CYP3A5*1 allele had a lower sirolimus C_0/D ratio compared with those with a homozygous CYP3A5*3 genotype (p < 0.05). No significant differences of sirolimus C_0/D ratios were observed among various ABCB11236C>T, 2677G>T/A and 3435C>T genotype groups. However, haplotype analysis including ABCB1 1236C>T, 2677G>T/A and 3435C>T SNPs showed that the mean sirolimus C_0/D of subjects carrying the CGC/CGC diplotype was about 30% lower compared with those carrying the CGC/TTT or TTT/TTT diplotype, whether or not they expressed the CYP3A5 (p < 0.05). These results demonstrated that the haplotype of ABCB1 might be a better index for the prediction of sirolimus blood concentration than single SNPs. Genotyping of ABCB1 and CYP3A5 might help to optimize individualized sirolimus treatments for Chinese renal transplant recipients.