title: ABCB1 haplotype influences the sirolimus dose requirements in Chinese renal transplant recipients.
abstract: Sirolimus, an immunosuppressive drug used to prevent organ rejection after renal transplantation, has a narrow therapeutic index and a large inter-individual variability of pharmacokinetics. The aim of this study was to analyse the dose-normalized trough blood concentrations (C0 /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 C0 /D ratio of sirolimus. The patients bearing at least one CYP3A5*1 allele had a lower sirolimus C0/D ratio compared with those with a homozygous CYP3A5*3 genotype (p < 0.05). No significant differences of sirolimus C0/D ratios were observed among various ABCB1 1236C>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 C0/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.
authors.affiliation: Department of Clinical Pharmacology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lee
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Lu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D044466:Asian People; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus
keywords: ABCB1; CYP3A5; polymorphism; renal transplant; sirolimus