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Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P‐glycoprotein
Author(s) -
Kurata Yasuo,
Ieiri Ichiro,
Kimura Miyuki,
Morita Toshihiro,
Irie Shin,
Urae Akinori,
Ohdo Shigehiro,
Ohtani Hisakazu,
Sawada Yasufumi,
Higuchi Shun,
Otsubo Kenji
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.126177
Subject(s) - digoxin , bioavailability , pharmacokinetics , pharmacology , p glycoprotein , drug interaction , chemistry , medicine , antibiotics , biochemistry , heart failure , multiple drug resistance
Objective Our objective was to quantitate the contribution of the genetic polymorphism of the human MDR1 gene to the bioavailability and interaction profiles of digoxin, a substrate of P‐glycoprotein. Methods The pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups (n = 5 each) on the basis of genotyping for the MDR1 gene, in a 4‐dose study after single doses of digoxin alone (0.5 mg orally and intravenously) and coadministered with clarithromycin (400 mg orally for 8 days). The dose of digoxin was reduced during the clarithromycin phase (0.25 mg orally and intravenously). Results The bioavailability of digoxin in G/G2677C/C3435, G/T2677C/T3435, and T/T2677T/T3435 subjects were 67.6% ± 4.3%, 80.9% ± 8.9%, and 87.1% ±8.4%, respectively, and the difference betweenG/G2677C/C3435 and T/T2677T/T3435 subjects was statistically significant ( P <.05). The MDR1 variants were also associated with differences in disposition kinetics of digoxin, with the renal clearance being almost 32% lower in T/T2677T/T3435 subjects (1.9 ± 0.1 mL/min per kilogram) than G/G2677C/C3435 subjects (2.8 ± 0.3 mL/min per kilogram), and G/T2677C/T3435 subjects having an intermediate value (2.1 ± 0.6 mL/min per kilogram). Coadministration of clarithromycin did not consistently affect digoxin clearance or renal clearance. However, a significant increase in digoxin bioavailability was observed in G/G2677C/C3435subjects (67.6% ± 4.3% versus 85.4% ± 6.1%; P < .05) but not inthe other2 genotype groups. Conclusion The allelic variants in the human MDR1 gene are likely to be associated with altered absorption and/or disposition profiles of digoxin and P‐glycoprotein‐mediated drug interaction (Clin Pharmacol Ther 2002;72:209‐19.) Clinical Pharmacology & Therapeutics (2002) 72 , 209–219; doi: 10.1067/mcp.2002.126177