Effects of CYP2D6 genotypes on age-related change of flecainide metabolism: involvement of CYP1A2-mediated metabolism

摘要

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ? CYP2D6 is a main enzyme for flecainide metabolism in terms of the conversion of flecainide to m - O -dealkylated flecainide (MODF). ? Age-related reduction of flecainide metabolism cannot be explained by CYP2D6 alone, the activity of which is known to be practically unchanged by ageing. ? Flecainide metabolites including MODF have been found in plasma obtained from CYP2D6 poor metabolizers, suggesting that other CYPs may be involved in flecainide metabolism. WHAT THIS STUDY ADDS ? Age-related reduction in metabolic clearance of flecainide was remarkable in patients carrying CYP2D6 mutant alleles. ? An in vitro study using human liver microsomes revealed that CYP1A2 was involved in MODF formation in addition to CYP2D6. ? It is suggested that CYP1A2 plays an important role in flecainide metabolism in patients with poor CYP2D6-mediated metabolism. AIMS The aim of this study was to clarify the effects of CYP2D6 genotype on age-related change in flecainide metabolism in patients with supraventricular tachyarrhythmias. An in vitro study using microsomes was performed to identify other CYPs responsible for age-related change in flecainide metabolism. METHODS The study population comprised 111 genotyped patients: CYP2D6-homozygous extensive metabolizers (hom-EMs, n = 34), heterozygous EMs (het-EMs, n = 56), and intermediate and poor metabolizers (IMs/PMs, n = 21). Serum concentrations of flecainide and its metabolites [ m - O -dealkylated flecainide (MODF) and m - O -dealkylated lactam of flecainide] were determined by use of a high-performance liquid chromatography. Metabolic ratio (MR) was expressed as serum concentrations of flecainide to its metabolites. In vitro formation of MODF was examined in human liver microsomes and cDNA-expressed CYP isoforms. RESULTS MR was higher in elderly patients (≥70 years) than in middle-aged patients ( CONCLUSIONS The results suggest that patients with poor CYP2D6-mediated metabolism (het-EMs and IMs/PMs) showed age-related reduction in flecainide metabolism because metabolism was taken over by CYP1A2, whose activity decreases with age.