title: Serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity.
abstract: The aims of this study were to clarify whether the ratio of S- to R-flecainide (S/R ratio) in the serum flecainide concentration was associated with the stereoselectivity of flecainide metabolism, and to investigate the effects of the cytochrome P450 (CYP) 2D6 (CYP2D6) genotype and CYP2D6 inhibitor on the serum flecainide S/R ratio. In vitro studies using human liver microsomes and cDNA-expressed CYP isoforms suggested that variability in the serum flecainide S/R ratio was associated with the stereoselectivity of CYP2D6-mediated flecainide metabolism. We examined the serum flecainide S/R ratio in 143 patients with supraventricular tachyarrhythmia. The S/R ratio was significantly lower in intermediate metabolizers and poor metabolizers (IMs/PMs) than in extensive metabolizers (EMs) identified by the CYP2D6 genotype. The cut-off value for the S/R ratio to allow the discrimination between CYP2D6 EMs and IMs/PMs was 0.99. The S/R ratio in patients with co-administration of bepridil, a potent CYP2D6 inhibitor, was lower than 0.99, regardless of the CYP2D6 genotype status. Other factors, including age, sex, body weight, and renal function, did not affect the serum flecainide S/R ratio. This study suggests that the serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity on co-administration of a CYP2D6 inhibitor.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: k-doki@mail.hosp.tsukuba.ac.jp.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Doki
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: yseki@md.tsukuba.ac.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sekiguchi
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: kuga@md.tsukuba.ac.jp.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kuga
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: kaonuma@md.tsukuba.ac.jp.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Aonuma
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: masatoh@md.tsukuba.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Homma
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D015764:Bepridil; D029402:Bignoniaceae / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005424:Flecainide / Q000097:blood*; D005838:Genotype; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D013610:Tachycardia / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D013617:Tachycardia, Supraventricular / Q000097:blood / Q000188:drug therapy / Q000235:genetics
chemical_list: D000889:Anti-Arrhythmia Agents; D018076:DNA, Complementary; D015764:Bepridil; D019389:Cytochrome P-450 CYP2D6; D005424:Flecainide
keywords: CYP2D6; CYP2D6 inhibitor; Flecainide; Genotype; S/R ratio