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Objective Sirolimus is an immunosuppressive drug with a narrow therapeutic range and wide inter- individual variation in its pharmacokinetics. The aim of this study was to investigate the possible association of CYP3A5 and MDR1 genotype with sirolimus dose requirements in Chinese renal transplant recipients.Methods Genotyping of CYP3A5*3 and MDR1 1236OT, 2677G>T/A, 3435OT was performed by SNaPShot multiplex assay in 85 Chinese renal transplant recipients who treated with sirolimus at least for 3 months.alleles. Their blood concentrations of sirolimus were determined with HPLC. Dose requirements to achieve target blood concentrations were compared among patients according to allelic status of CYP3A5 and MDRl.Results The average sirolimus concentration/dose ratio in patients bearing at least one CYP3A5*1 allele was significantly lower than that of those with a homozygous CYP3A5*3 genotype (240.06 + 75.19 vs. 289.69+102.09 ng/ml per mg/kg, p < 0.05), ultimately requiring significantly higher sirolimus doses to reach the same target range (0.029 + 0.009 vs 0.024+0.009 mg/kg, p<0.05). And similar result was also observed between the patients with wild-type genotype (CC) and those with heterozygous/homozygous variants (CT/ TT) 3435C>T of MDR1. The mean dose required to obtain the target trough concentration was 0.030 + 0.007 and 0.025 + 0.009 mg/kg respectively (p<0.05); the average concentration/dose ratios was 232.12 +65.73 and 280.51 +99.68 ng/ml per mg/kg respectively (p<0.05). Conclusion Besides CYP3A5*3, MDR1 3435C>T polymorphism is associated with sirolimus pharmacokinetics and dose requirements in Chinese renal transplant recipients. Genotyping for CYP3A5*3 and MDR1 3435C>T may help optimal individualization of sirolimus therapy for adequate immunosuppression.