Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein.
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 between G/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/C3435 subjects (67.6% +/- 4.3% versus 85.4% +/- 6.1%; P <.05) but not in the other 2 genotype groups.


CONCLUSIONS
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
Division of Pharmaceutical Sciences, Department of Clinical Pharmacokinetics, Graduate School, Kyushu University, Kyushu, Japan.
Yasuo
Y
Kurata
Ichiro
I
Ieiri
Miyuki
M
Kimura
Toshihiro
T
Morita
Shin
S
Irie
Akinori
A
Urae
Shigehiro
S
Ohdo
Hisakazu
H
Ohtani
Yasufumi
Y
Sawada
Shun
S
Higuchi
Kenji
K
Otsubo
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D001682:Biological Availability; D002316:Cardiotonic Agents / Q000493:pharmacokinetics; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D007275:Injections, Intravenous; D007564:Japan; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012016:Reference Values
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System; D017291:Clarithromycin