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Effect of CYP2D6 phenotype and metoprolol pharmacokinetics on adverse effects
Author(s) -
Beitelshees A. L.,
Zineh I.,
Gaedigk A.,
Leeder J. S.,
Walker J. R.,
Eberst K.,
Timmerbeil B. S.,
Lobmeyer M.,
Pauly D. F.,
Johnson J. A.
Publication year - 2004
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 - 10.1016/j.clpt.2003.11.359
Subject(s) - metoprolol , cyp2d6 , pharmacokinetics , pharmacology , adverse effect , medicine , phenotype , biology , genetics , cytochrome p450 , metabolism , gene
We hypothesized that metoprolol adverse effects (AEs) would be dependent on S‐metoprolol concentration (Cp) and CYP2D6 phenotype. Hypertensive subjects took metoprolol bid with weekly titration to response, maximum dose, or intolerable AEs. Steady‐state Cp was measured and AUC determined. AEs were classified as “dose‐limiting” (DL) or “general” (G, defined as AE consistent with known pharmacology, likely to cause noncompliance or a change in drug). Genotyping included assays for *2, *3, *4, *5, *6, *9, *10, *17, *29, *40, *41 and gene duplications to classify subjects as extensive, intermediate, or poor metabolizers (EM, IM or PM). Further, we assigned activity scores (AS) between 0 and 3 based on the number of functional or partially functional alleles. Fifty patients (42 EM, 4 IM, and 4 PM) were analyzed. Daily doses ranged from 25 to 400 mg. Sixteen (n=8) and 46% (n=23) of subjects experienced DL and G‐AEs, respectively. Of patients in the highest AUC quartile, 33% had a G‐AE, compared to 77% in the lowest quartile (p<0.05). Trends for DL‐AEs were similar. CYP2D6 phenotype was not associated with AEs. AUC, Cl/F, t1/2, and enantiomeric ratio were expectedly associated with CYP2D6 phenotype and AS (p<0.02). Contrary to widely held beliefs, metoprolol AEs were not related to high Cp, 2D6 phenotype or AS. While CYP2D6 genotyping may predict pharmacokinetic drug exposure, a priori genotyping may not be effective in reducing AEs with metoprolol in hypertension. Clinical Pharmacology & Therapeutics (2004) 75 , P94–P94; doi: 10.1016/j.clpt.2003.11.359

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