Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein

Yasuo Kurata, Ichiro Ieiri, Miyuki Kimura, Toshihiro Morita, Shin Irie, Akinori Urae, Shigehiro Ohdo, Hisakazu Ohtani, Yasufumi Sawada, Shun Higuchi, Kenji Otsubo

Research output: Contribution to journalArticle

245 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
Pages (from-to)209-219
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume72
Issue number2
DOIs
Publication statusPublished - 2002 Aug
Externally publishedYes

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Digoxin
P-Glycoprotein
Biological Availability
Genes
Clarithromycin
Kidney
Genetic Polymorphisms
Drug Interactions
Healthy Volunteers
Pharmacokinetics
Genotype

ASJC Scopus subject areas

  • Pharmacology

Cite this

Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. / Kurata, Yasuo; Ieiri, Ichiro; Kimura, Miyuki; Morita, Toshihiro; Irie, Shin; Urae, Akinori; Ohdo, Shigehiro; Ohtani, Hisakazu; Sawada, Yasufumi; Higuchi, Shun; Otsubo, Kenji.

In: Clinical Pharmacology and Therapeutics, Vol. 72, No. 2, 08.2002, p. 209-219.

Research output: Contribution to journalArticle

Kurata, Y, Ieiri, I, Kimura, M, Morita, T, Irie, S, Urae, A, Ohdo, S, Ohtani, H, Sawada, Y, Higuchi, S & Otsubo, K 2002, 'Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein', Clinical Pharmacology and Therapeutics, vol. 72, no. 2, pp. 209-219. https://doi.org/10.1067/mcp.2002.126177
Kurata, Yasuo ; Ieiri, Ichiro ; Kimura, Miyuki ; Morita, Toshihiro ; Irie, Shin ; Urae, Akinori ; Ohdo, Shigehiro ; Ohtani, Hisakazu ; Sawada, Yasufumi ; Higuchi, Shun ; Otsubo, Kenji. / Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. In: Clinical Pharmacology and Therapeutics. 2002 ; Vol. 72, No. 2. pp. 209-219.
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abstract = "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. 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.",
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T1 - Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein

AU - Kurata, Yasuo

AU - Ieiri, Ichiro

AU - Kimura, Miyuki

AU - Morita, Toshihiro

AU - Irie, Shin

AU - Urae, Akinori

AU - Ohdo, Shigehiro

AU - Ohtani, Hisakazu

AU - Sawada, Yasufumi

AU - Higuchi, Shun

AU - Otsubo, Kenji

PY - 2002/8

Y1 - 2002/8

N2 - 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. 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.

AB - 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. 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.

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