Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype.

Gross, Annette S.; Mikus, Gerd; Fischer, Christine; Hertrampf, R; Gundert‐Remy, Ursula; Eichelbaum, Michel

doi:10.1111/j.1365-2125.1989.tb03542.x

Cited by 49 publications

(19 citation statements)

References 25 publications

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“…This suggests that the main enzyme that metabolizes flecainide is CYP2D6. Some reports, however, have suggested that other CYP isozymes are involved in flecainide metabolism, because MODF and MODLF can be detected in plasma even in CYP2D6 PMs [7–9], although the responsible enzymes have not yet been identified.…”

Section: Introductionmentioning

confidence: 99%

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

Doki

Homma

Kuga

et al. 2009

Brit J Clinical Pharma

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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.

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Section: Introductionmentioning

confidence: 99%

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

Doki

Homma

Kuga

et al. 2009

Brit J Clinical Pharma

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“…. The calculated pharmacokinetic parameters listed in Table were in accordance with previous reports (Gross et al ., , ). S / R ratios of elimination half‐life, AUC 0–24 , and amount excreted in urine were lowest in subject 3.…”

Section: Resultsmentioning

confidence: 99%

“…The sensitivity of the assay was sufficient to determine flecainide enantiomers in pharmacokinetic study and routine therapeutic drug monitoring (TDM; Tables and ) compared with previous indirect (Turgeon et al ., ) and direct (Hanada et al ., ) methods equipped with fluorescence detector. Assay precision was confirmed in intra‐ and inter‐day validation experiments and was also comparable with that of previous methods (Table ; Gross et al ., ; Alessi‐Severini et al ., ; Turgeon et al ., ; Hanada et al ., ). Therefore, the present method is sufficiently sensitive and precise in the concentration range required for pharmacokinetic study and flecainide TDM (Table ).…”

Section: Discussionmentioning

confidence: 99%

Stereoselective analysis of flecainide enantiomers using reversed‐phase liquid chromatography for assessing CYP2D6 activity

Doki

Sekiguchi

Kuga

et al. 2014

Biomedical Chromatography

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Stereoselective analyses of flecainide enantiomers were performed using reversed-phase high-performance liquid chromatography (HPLC) equipped with a polysaccharide-based chiral column (Chiralpak AS-RH) and fluorescence detector. Excitation and emission wavelengths were set at 300 and 370 nm, respectively. Flecainide enantiomers in serum and urine were extracted using diethyl ether. The mobile phase solution, comprising 0.1 m potassium hexafluorophosphate and acetonitrile (65:35, v/v), was pumped at a flow rate of 0.5 mL/min. The recoveries of flecainide enantiomers were greater than 94%, with the coefficients of variation (CVs) <6%. The calibration curves of flecainide enantiomers in serum and urine were linear in the concentration range 5-500 ng/mL and 0.75-15 µg/mL (r > 0.999), respectively. CVs in intra-day and inter-day assays were 1.8-5.8 and 3.4-7.5%, respectively. In a pharmacokinetic study, the ratios of (S)- to (R)-flecainide (S/R ratio) in the area under the curve and the amount of flecainide enantiomers excreted in urine were lower in a subject carrying CYP2D6*10/*10 than in subjects carrying CYP2D6*1/*2. The S/R ratio of trough serum flecainide concentration ranged from 0.79 to 1.16 in patients receiving oral flecainide. The present HPLC method can be used to assess hepatic flecainide metabolism in a pharmacokinetic study and therapeutic drug monitoring.

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“…It follows that the influence of the sparteine/debrisoquine polymorphism on flecainide disposition may be particularly important in patients with renal impairment. Although small differences in the stereoselective disposition of flecainide have been observed between phenotypes (Gross et al 1989), they should not contribute to differences in response between poor and extensive metabolisers, since the enantiomers have similar antiarrhythmic potency. Data are lacking on the relationship between polymorphic oxidation and the clinical response to flecainide.…”

Section: Cardiovascular Drugsmentioning

confidence: 95%

Genetically Determined Adverse Drug Reactions Involving Metabolism

Lennard

1993

Drug Safety

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Genetic factors represent an important source of interindividual variation in drug response. Relatively few adverse drug effects with a pharmacodynamic basis are known, and most of the well characterised inherited traits take the form of genetic polymorphisms of drug metabolism. Monogenic control of N-acetylation, S-methylation and cytochrome P450-catalysed oxidation of drugs can have important clinical consequences. Individuals who inherit an impaired ability to perform one or more of these reactions may be at an increased risk of concentration-related toxicity. There is a strong case for phenotyping before starting treatment with a small number of drugs that are polymorphically N-acetylated or S-methylated. However, the issue of clinical significance is perhaps most relevant for the debrisoquine oxidation polymorphism, which is mediated by cytochrome CYP2D6 and which determines the pharmacokinetics of many commonly used drugs. Phenotypic poor metabolisers of debrisoquine (8% of Caucasian populations) taking standard doses of some tricyclic antidepressants, neuroleptics or antiarrhythmic drugs may be particularly prone to adverse reactions. Similarly, clinically relevant drug interactions between these drugs and other substrates of cytochrome CYP2D6 may occur in the majority of the population who are extensive metabolisers. However, it is clear that in the majority of cases there is a need for controlled prospective studies to determine clinical significance. Accordingly, routine debrisoquine phenotyping or genotyping before beginning drug treatment is difficult to justify at present, although it may be helpful in individual cases. When prescribing drugs whose metabolism is polymorphic alone or in combination, careful titration of the dose in both phenotypic groups is prudent. In some cases it will be preferable to use alternative therapy to avoid the risk of adverse drug reactions.

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Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype.

Cited by 49 publications

References 25 publications

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

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

Stereoselective analysis of flecainide enantiomers using reversed‐phase liquid chromatography for assessing CYP2D6 activity

Genetically Determined Adverse Drug Reactions Involving Metabolism

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