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.
Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
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J
Matthaei
Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
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Brockmöller
Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
M V
MV
Tzvetkov
Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
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Sehrt
Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
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Sachse-Seeboth
Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark.
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JB
Hjelmborg
Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark.
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Möller
Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark.
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U
Halekoh
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and Department of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
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Hofmann
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and Department of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.|Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
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Schwab
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and Department of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
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Kerb
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D040941:Heredity; D006801:Humans; D007262:Infusions, Intravenous; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077786:Torsemide; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics; D055815:Young Adult
D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D000077786:Torsemide