Heritability of metoprolol and torsemide pharmacokinetics


Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated.


Projects: G2: Clinical Translation to Non-Invasive Volunteer Setting, G3: Clinical Translation to Pharmaceutical Drug Development

Clin Pharmacol Ther
Clin Pharmacol Ther. 2015 Sep 7. doi: 10.1002/cpt.258.
8th Sep 2015

J. Matthaei, J. Brockmoller, M. V. Tzvetkov, D. Sehrt, C. Sachse-Seeboth, J. B. Hjelmborg, S. Moller, U. Halekoh, U. Hofmann, M. Schwab, R. Kerb

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[Ute Hofmann] [Matthias Schwab] [Reinhold Kerb]

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Views: 746
  • Created: 17th Dec 2015 at 11:46

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