Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1998-09

AUTHORS

R. Koytchev, R.-G. Alken, V. Vlahov, V. Kirkov, R. Kaneva, U. Thyroff-Friesinger, E. Rehak

ABSTRACT

AIM: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D6*1/CYP2D6*1) and heterozygous (CYP2D6*1/CYP2D6*4) Caucasians. METHODS: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D6*3 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 randomized, cross-over fashion one of the three formulations compared. Each formulation contained 200 mg metoprolol tartrate/(tablet). In each of the three periods of the trial, one of the formulations was administered under fasting conditions in the morning on 4 consecutive days. Blood for quantification of metoprolol was drawn immediately before the last dose and in selected time intervals thereafter. A sensitive and specific high-performance liquid chromatography (HPLC) method with fluorescence detection was applied for the quantification of metoprolol. Pharmacokinetic parameters were determined for each subject and statistically compared in two groups of 16 homozygous (CYP2D6*1/CYP2D6*1) and six heterozygous (CYP2D6*1/CYP2D6*4) volunteers. RESULTS: Significant differences between homozygous and heterozygous individuals were observed for all pharmacokinetic parameters. The AUC in the course of one those interval of 24 h (AUCtau), minium steady-state concentration (C(min)ss) and average steady-state concentration (C(av)ss) values for heterozygous individuals were more than twice those of individuals. Significantly higher values for C(max)ss, t1/2, half-value duration (HVD) and mean residence time (MRT) were also observed in heterozygous volunteers. The higher concentrations of metoprolol in heterozygous individuals also had pharmacodynamic consequences, namely, greater heart rate and blood pressure reduction. More... »

PAGES

469-474

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s002280050495

DOI

http://dx.doi.org/10.1007/s002280050495

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1039087672

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/9776437


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