title: Multi-drug resistance gene-1 (MDR-1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by C0 or C2 measurements.
abstract: The intestinal efflux pump P-glycoprotein (P-gp), the product of the multi-drug resistance-1 (MDR-1) gene, significantly influences the pharmacokinetics of several drugs. Ciclosporin is a substrate for P-gp and is metabolized by cytochrome P450 (CYP) 3A enzymes. P-gp activity is affected by several known single nucleotide polymorphisms (SNPs) and haplotypes. MDR-1 genotypes of SNPs C1236T, G2677T/A and C3435T, as well as haplotypes C-G-C and T-T-T and CYP3A5*1 genotype (predictive of CYP3A5 expression), were related to ciclosporin blood concentrations measured at both 0 and 2 h after drug dosing in 197 stable renal transplant patients. Significant differences (of a magnitude unlikely to be relevant clinically) in dose-normalized blood ciclosporin concentrations were found only between MDR-1 genotypes of the C1236T SNP and between haplotype groups C-G-C and T-T-T in patients that were expressers of CYP3A5. MDR-1 SNPs and haplotypes and also CYP3A5*1 genotype, do not appear to have a major influence on ciclosporin pharmacokinetics.
authors.affiliation: Analytical Unit, Cardiac & Vascular Science, St George's University of London, London, UK. frederic@sgul.ac.uk
authors.forename: Salim
authors.initials: S
authors.lastname: Fredericks
authors.forename: AnaMaria
authors.initials: A
authors.lastname: Jorga
authors.forename: Iain A M
authors.initials: IA
authors.lastname: MacPhee
authors.forename: Sandrine
authors.initials: S
authors.lastname: Reboux
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Shiferaw
authors.forename: Michelle
authors.initials: M
authors.lastname: Moreton
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Carter
authors.forename: David W
authors.initials: DW
authors.lastname: Holt
authors.forename: Atholl
authors.initials: A
authors.lastname: Johnston
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008875:Middle Aged
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A