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. AIMSThe 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. METHODSThe 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. RESULTSMR was higher in elderly patients (Ն70 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. CONCLUSIONSThe 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.

Effects of CYP1A2 Gene Polymorphisms on Antipyrine CYP1A2-Dependent Metabolism

“…The following models were obtained: NAP=-0.353 AGE+0.109 COT+0.072 CYP1A2F+ 0.004 CYP1A2D (R 2 =0.131, F=1.24 p<0.310, SEE 4 All the resultant models indicate (with a different level of signifi cance) a feedback between the level of the main AP metabolites and volunteers' ages, which is in line with available data on age-associated reduction of functional activity of the majority of cytochrome P-450 isoforms, specifi cally, of CYP1A2 [8].…”

CYP2D6 genotype affects age-related decline in flecainide clearance

“…3), which corresponded to a deficient or decreased enzyme activity: 22.1% reduction in hetEMs and 49.5% reduction in IMs/PMs groups, but no change in the hom-EMs group, even though the CYP2D6 activity is not affected by aging [3,4]. Two metabolic enzymes, CYP2D6 and CYP1A2, are responsible for the conversion of flecainide to MODF, where CYP2D6 is the primary pathway and CYP1A2 is the secondary pathway in hepatic metabolism [11]. A marked reduction in agerelated metabolic CL/F in patients with CYP2D6 mutant alleles may be caused by the switching of the primary enzyme involved in flecainide metabolism from CYP2D6 to CYP1A2; the activity of CYP1A2 was reduced in an age-dependent manner.…”

“…We reported a significant age-related decline in flecainide metabolism in patients carrying CYP2D6 mutant alleles compared with those carrying the wild-type alleles [11]. It was suggested that the CYP2D6 genotype was associated with the magnitude of the age-related reduction in flecainide metabolism.…”

“…A possible mechanism for the age-related decline in flecainide metabolism in the patients with reduced CYP2D6-mediated metabolism is because of switching of the principle metabolic enzyme from CYP2D6 to CYP1A2 whose activity is known to decrease with age ( Fig. 1) [11].…”

“…Flecainide undergoes renal excretion and hepatic metabolism by its conversion to m-O-dealkylated flecainide (MODF) and subsequent oxidation to m-O-dealkylated lactam [9,10]. The formation of MODF is catalyzed by both CYP2D6 and CYP1A2 [11].…”