MDR1 Genotype-Related Pharmacokinetics of Digoxin After Single Oral Administration in Healthy Japanese Subjects

• Published in: Pharmaceutical research Vol. 18; no. 10; pp. 1400 - 1404
• Main Authors: Sakaeda, Toshiyuki, Nakamura, Tsutomu, Horinouchi, Masanori, Kakumoto, Mikio, Ohmoto, Nobuko, Sakai, Toshiyuki, Morita, Yoshinori, Tamura, Takao, Aoyama, Nobuo, Hirai, Midori, Kasuga, Masato, Okumura, Katsuhiko
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.10.2001; Springer Nature B.V
• Subjects: Adult; Aged; Biological and medical sciences; Cardiotonic agents; Cardiotonic Agents - pharmacokinetics; Cardiovascular system; Digoxin - pharmacokinetics; DNA - biosynthesis; DNA - genetics; Drug dosages; Enzymes; Exons - genetics; Female; Gene Frequency; Genes, MDR - genetics; Genotype; Genotype & phenotype; Humans; Japan; Male; Medical sciences; Middle Aged; Oral administration; Pharmacokinetics; Pharmacology. Drug treatments; Polymerase chain reaction; Polymorphism; Polymorphism, Restriction Fragment Length; Reverse Transcriptase Polymerase Chain Reaction; Japan; Human; Cardiotonic agent; Digoxin; Single dose; Oral administration; Genotype; Normal; Absorption; Multiple resistance; Serum; Glycoside; Mutation; Pharmacokinetics; Digitalis drug
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1012244520615

To evaluate the MDR1 genotype frequency in the Japanese population and to study the relationship between the MDR1 genotype and the pharmacokinetics of digoxin after single oral administration in healthy subjects. The MDR1 genotype at exon 26 was determined in 114 healthy volunteers by polymerase chain reaction-restriction fragment length polymorphism. The serum concentration-time profile of digoxin was examined after single oral administration at a dose of 0.25 mg. 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 with 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 distribution. The serum concentration of digoxin after a single oral administration increased rapidly, attaining a steady state in all subjects; however, it was lower in the subjects harboring the T-allele. AUC0-4 h values (+/-SD) were 4.11 +/- 0.57, 3.20 +/- 0.49. and 3.27 +/- 0.58 ng h/ml, respectively, with a significant difference between C/C and C/T or T/T. The serum concentration of digoxin after single oral administration was lower in the subjects harboring a mutant allele (C3435T) at exon 26 of the MDR1 gene.