MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects

Purpose. To evaluate the MDR1 genotype frequency in the Japanese population and to study the relationship between the MDR1 genotype and the pharmacoki netics of digoxin after single oral administration in healthy subjects. Methods. The MDR1 genotype at exon 26 was determined in 114 healthy volunte ers by polymerase chain reaction-restriction fragment length polymorphism. The serum concentration-time profile of digoxin was examined after single o ral administration at a dose of 0.25 mg. Results. It was found that 35.1 % (40/114) of subjects were homozygous for the wild-type allele (C/C), 52.6 % (60/114) were compound heterozygotes wit h a mutant T-allele (C3435T) (C/T), and 12.3 % (14/114) were homozygous for the mutant allele (T/T). There was no effect of gender or age on the distr ibution. The serum concentration of digoxin after a single oral administrat ion increased rapidly, attaining a steady state in all subjects; however, i t was lower in the subjects harboring the T-allele. AUC(0.4) (h) values (+/ -SD) were 4.11 +/- 0.57, 3.20 +/- 0.49, and 3.27 +/- 0.58 ng h/ml, respecti vely, with a significant difference between C/C and C/T or T/T. Conclusions. The serum concentration of digoxin after single oral administr ation was lower in the subjects harboring a mutant allele (C3435T) at exon 26 of the MDR1 gene.