C3435T mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects.
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.
Min
David I
DI
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
Ellingrod
Vicki L
VL
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
D016572:Cyclosporine; D007166:Immunosuppressive Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1