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

Abstract

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 (<70 years). The increase of MR in elderly patients differed among CYP2D6 genotypes: 1.6-fold in het-EMs [4.3, 95% confidence interval (CI) 2.8, 5.7 vs. 2.7, 95% CI 2.3, 3.1, P < 0.05], 1.5-fold in IMs/PMs (6.0, 95% CI 4.5, 7.6 vs. 4.1, 95% CI 2.9, 5.4, P < 0.05), and no change in hom-EMs. The in vitro study using microsomes revealed that both CYP2D6 and CYP1A2 were involved in the formation of MODF. MODF formation in CYP2D6 PM microsomes increased as CYP1A2 activity increased. 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. © 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society.