INFLUENCE OF THE CYTOCHROME P4502D6-ASTERISK-4 ALLELE ON THE PHARMACOKINETICS OF CONTROLLED-RELEASE METOPROLOL

Aim: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP 2D6 allele (CYP2D61/CYP2D6'*1) and heterozygous (CYP2D6*1/CYP2D6*4) C aucasians. Method's: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP 2D63 and CYP2D6*4) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomi zed, cross-over fashion one of the three formulations compared. Each f ormulation contained 200 mg metoprolol tartrate/(tablet). In each of t he three periods of the trial, one of the formulations was administere d under fasting conditions in the morning on 4 consecutive days. Blood for quantification of metoprolol was drawn immediately before the las t dose and in selected time intervals thereafter. A sensitive and spec ific high-performance liquid chromatography (HPLC) method with fluores cence detection was applied for the quantification of metoprolol. Phar macokinetic parameters were determined for each subject and statistica lly compared in two groups of 16 homozygous (CYP2D61/CYP2D6*1) and si x heterozygous (CYP2D61/CYP2D6*4) volunteers. Results: Significant di fferences between homozygous and heterozygous individuals were observe d for all pharmacokinetic parameters. The AUC in the course of one tho se interval of 24 h (AUC(tau)), minium steady-state concentration (C-m in(ss)) and average steady-state concentration (C-av(ss)) values for h eterozygous individuals were more than twice those of individuals. Sig nificantly higher values for C-max(ss), t(1/2), half-value duration (H VD) and mean residence time (MRT) were also observed in heterozygous v olunteers. The higher concentrations of metoprolol in heterozygous ind ividuals also had pharmacodynamic consequences, namely, greater heart rate and blood pressure reduction.