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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 |
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