¹Department of Pharmacy Practice, Center for Pharmacogenomics, and Division of Cardiovascular Medicine, University of Florida, Gainesville; Division of Pediatric Clinical Pharmacology and Medical Toxicology and Section of Developmental Pharmacology and Experimental Therapeutics, Children's Mercy Hospital, and Department of Pediatrics, University of Missouri–Kansas City, Kansas City; and Orchid BioSciences, Inc, Princeton

Correspondence: Julie A. Johnson, PharmD, University of Florida College of Pharmacy, Department of Pharmacy Practice, PO Box 100486 Gainesville, FL 32610 E-mail: johnson@cop.ufl.edu

^*The authors have no financial or personal conflicts of interest to disclose.

^*This work was supported by grants from the National Institutes of Health National Heart, Lung, and Blood Institute (HL64691) and the University of Florida General Clinical Research Center (M01-RR00082).

Received 26 May 2004; Accepted 11 August 2004.

Abstract

Objective: -Blocker use can be associated with adverse effects that may have an impact on adherence or harm patients. The commonly prescribed -blocker metoprolol is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 enzyme, resulting in widely variable drug exposure. We investigated whether metoprolol plasma concentrations, CYP2D6 polymorphisms, or genotype-derived phenotype was associated with adverse effects or efficacy in patients with hypertension.

Methods: Fifty hypertensive patients received metoprolol by use of a dose-titration algorithm until target blood pressure was reached, intolerable side effects occurred, or maximal daily dose was achieved. CYP2D6 genotype was determined by methods based on polymerase chain reaction–restriction fragment length polymorphism and included 19 allelic variants. Patients were assigned to standard phenotype groups on the basis of genotype. Patients were also assigned activity scores based on functional activity of the alleles. General and dose-limiting adverse events and blood pressure responses were analyzed in relation to metoprolol steady-state pharmacokinetic profile and CYP2D6 genotype–derived phenotype.

Results: Poor metabolizers had a significantly longer elimination half-life, higher S-metoprolol area under the plasma concentration–time curve (AUC), and lower oral clearance (P .007 for all parameters). There was a 29.6-fold variability in AUC among extensive metabolizers, which was largely explained by CYP2D6 activity scores (P = .032 for ordered differences in AUC by activity score among extensive metabolizers). Overall general and dose-limiting adverse event rates were 46% and 14%, respectively. General adverse event rates did not differ by AUC quartile (66.7% [95% confidence interval (CI), 35.4%-88.7%] and 41.7% [95% CI, 16.5%-71.4%] in the lowest and highest quartiles, respectively; P = .09 among all quartiles). Dose-limiting adverse event rates were also not different by AUC quartile (16.7% [95% CI, 2.9%-49.1%] and 8.3% [95% CI, 0.4%-40.2%] in the lowest and highest quartiles; P = .35 among all quartiles). Furthermore, adverse event rates did not differ by activity %scores or between extensive, intermediate, or poor metabolizers. Antihypertensive response rate and blood pressure changes also were not influenced by differences in plasma concentrations or CYP2D6 genotypes.

Conclusions: As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and -blocker–induced adverse effects or efficacy.