Cytochrome P450 2D6 phenotype and genotype in hypertensive patients on long-term therapy with metoprolol

Abstract

Objective:The aim was to compare cytochrome P450 2D6 phenotype and genotype using metoprolol as a probe drug. Further, to investigate the infl uence of P450 2D6 activity on metoprolol pharmacokinetics and pharmacodynamics in patients on metoprolol therapy. Background: Cytochrome P450 2D6 is a highly polymorphic enzyme that contributes to the variability of metoprolol. However, environmental factors also modify drug disposition. Methods: Forty-nine hypertensive patients were enrolled. Serum metoprolol and α-hydroxymetoprolol concentrations, resting heart rate were measured before, 1, 3 and 4 hours post-dose. Results: Signifi cantly higher normalized metoprolol serum concentrations, normalized metoprolol AUC 0-4 and metoprolol oral clearance were observed in patients with lower P450 2D6 metabolic activity. A trend towards a lower resting heart rate before metoprolol intake was also observed in this group of patients. The differences in metoprolol disposition were more expressed when P450 2D6 phenotype instead of genotype was determined. Conclusion: Signifi cant variations exist in metoprolol disposition in hypertensive patients. Both genotyping and phenotyping provides a valuable method in determining the enzymatic activity and in optimising metoprolol therapy (Tab. 3, Fig. 8, Ref. 35 The cytochromes P450 (P450) are the superfamily of hemecontaining monooxygenases playing an important role in the biotransformation of both endogenous and exogenous compounds (1). Most human P450s that participate in drug metabolism show a considerable interindividual variability in most humans in both levels of expression and catalytic activity. This variability is due to both environmental and genetic factors (2). P450 2D6 (known as debrisoquine/sparteine hydroxylase) is a highly polymorphic enzyme (3). To date, more than 100 different P450 2D6 allelic variants and sub-variants have been defi ned (4). In general, genotypes may be differentiated into four subgroups: poor (PM), intermediate (IM), extensive (EM) and ultrarapid (UM) metabolizers. Subjects with a PM genotype lack any functional allele, whereas EMs have two and UM subjects have more than two functional alleles. Subjects with IM genotype are heterozygous for a specifi c variant allele and/or possess alleles with reduced activity (4). The frequency of individual variants of P450 2D6 shows a marked interethnic difference. In white European populations, the percentage of PM varies from 3.2 % (Finish) to 11.7 % (Germans), but PMs constitute less than 1 % of Asian subjects (6, 7). Beside the genetic variability, environmental factors such as dietary habits (8) or drug interactions may also modify drug disposition (9). In vivo P450 phenotyping has proven to be very successful in predicting the actual enzymatic activity. It is based on administration of an adequate probe drug followed by measurement and calculation of metabolic ratio (MR) of a parent compound to its metabolite mediated by P450 of interest. The MR of P450 2D6 probe drugs shows bimodal or even trimodal d...