title: Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors.
abstract: The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.
authors.affiliation: Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden. Mia.Wadelius@medsci.uu.se
authors.forename: M
authors.initials: M
authors.lastname: Wadelius
authors.forename: K
authors.initials: K
authors.lastname: Sörlin
authors.forename: O
authors.initials: O
authors.lastname: Wallerman
authors.forename: J
authors.initials: J
authors.lastname: Karlsson
authors.forename: Q-Y
authors.initials: QY
authors.lastname: Yue
authors.forename: P K E
authors.initials: PK
authors.lastname: Magnusson
authors.forename: C
authors.initials: C
authors.lastname: Wadelius
authors.forename: H
authors.initials: H
authors.lastname: Melhus
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency / Q000187:drug effects / Q000502:physiology; D014644:Genetic Variation / Q000187:drug effects; D006470:Hemorrhage / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A