title: C3435T mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects.
abstract: To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 (MDR1) gene and cyclosporine pharmacokinetic parameters among healthy volunteers, the oral cyclosporine pharmacokinetic study was performed for 14 healthy subjects. Blood cyclosporine concentrations were measured by HPLC. Concentration-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the C3435T polymorphism of MDR1 gene using the PCR and a restriction digest. Each cyclosporine pharmacokinetic parameter was compared using the Mann-Whitney U test according to his or her P-gp genotype. There were seven (7) homozygous C/C, six (6) C/T, and one (1) homozygous T/T genotypes in these 14 healthy volunteers. According to their genotypes, mean t(max) 1.6 +/- 0.3 hours, mean C(max) 1337 +/- 329 ng/mL, mean Cl/F 66.5 +/- 18.3 L/h, and mean AUC 5642 +/- 1577 ng.h/mL in C/C group and mean t(max) 2.0 +/- 0.6 hours, mean C(max) 1540 +/- 721 ng/mL, mean Cl/F 55.2 +/- 18.9 L/h, and mean AUC 6902 +/- 1405 ng.h/mL in C/T+T/T group. Although Cmax and AUC in C/T and T/T group were 15% and 22% larger than those in C/C group, none of these parameter comparisons was statistically significant. There were no statistical differences in cyclosporine pharmacokinetics among different MDR1 genotypes in these 14 healthy subjects.
authors.affiliation: Division of Clinical and Administrative Pharmacy, College of Pharmacy, The University of Iowa, 118 Pharmacy Building, Iowa City, IA 52242, USA. david-min@uiowa.edu
authors.forename: David I
authors.initials: DI
authors.lastname: Min
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Ellingrod
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012016:Reference Values
chemical_list: D016572:Cyclosporine; D007166:Immunosuppressive Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1