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

Clin Transplant. 2007 Mar-Apr;21(2):252-7. doi: 10.1111/j.1399-0012.2006.00635.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Cyclosporine / administration & dosage*
  • Cyclosporine / blood
  • Cyclosporine / pharmacokinetics
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Female
  • Genes, MDR / genetics*
  • Genotype
  • Haplotypes
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics
  • Kidney Transplantation / immunology
  • Kidney Transplantation / physiology*
  • Middle Aged

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Immunosuppressive Agents
  • Cyclosporine
  • Cytochrome P-450 Enzyme System
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A