title: Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients.
abstract: Intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) both play a vital role in the metabolism of oral cyclosporine (CsA). We investigated the genetic polymorphisms in CYP3A4(promoter region and exons 5, 7 and 9) and MDR1 (exons 12, 21 and 26) genes and the impact of these polymorphisms on the pharmacokinetics of oral CsA in stable heart transplant patients (n = 14). CYP3A4 polymorphisms were rare in the Asian population and transplant patients. Haplotype analysis revealed 12 haplotypes in the Chinese, eight in the Malays and 10 in the Indians. T-T-T was the most common haplotype in all ethnic groups. The frequency of the homozygous mutant genotype at all three loci (TT-TT-TT) was highest in the Indians (31%) compared to 19% and 15% in the Chinese and Malays, respectively. In heart transplant patients, CsA exposure (AUC(0-4 h), AUC(0-12 h) and C(max)) was high in patients with the T-T-T haplotypes compared to those with C-G-C haplotypes. These findings suggest that haplotypes rather than genotypes influence CsA disposition in transplant patients.
authors.affiliation: Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Republic of Singapore. ctebal@nccs.com.sg
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
authors.forename: Sivathasan
authors.initials: S
authors.lastname: Cumaraswamy
authors.forename: Yin Bun
authors.initials: YB
authors.lastname: Cheung
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Zhou
authors.forename: Edmund J D
authors.initials: EJ
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001208:Asia; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D005006:Ethnicity; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D016027:Heart Transplantation / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D017931:DNA Primers; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human