title: Influence of proton pump inhibitors and VKORC1 mutations on CYP2C9-mediated dose requirements of vitamin K antagonist therapy: a pilot study.
abstract: Interindividual variations in dose requirements of oral vitamin K antagonists (VKA) are attributed to several factors, including genetic variant alleles of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9), but also interaction with co-medications. In this context, proton pump inhibitor (PPI)-related alterations of VKA maintenance dose requirements have been published. The present investigation aimed to test for an interaction profile of oral VKA-therapy and PPIs in relation to the CYP2C9 genotype. Median weekly stable VKA dose requirements over 1 year were recorded in 69 patients. Patients were genotyped for CYP2C9*2, CYP2C9*3, VKORC1c.-1639G>A and VKORC1c.174-136C>T and assessed for an association with PPI use and total VKA maintenance dose requirements. PPI users with CYP2C9 genetic variations required significantly lower weekly VKA maintenance doses than those with the wild-type genotype (t-test: P = 0·02). In contrast, in subjects without PPI use, the CYP2C9 genotype had no significant influence on oral VKA dose requirements. Further, the combined CYP2C9/VKORC1 genotype was a significant predictor for VKA dose requirements [linear regression: estimate: -1·47, standard error: 0·58 (P = 0·01)]. In conclusion, in carriers of CYP2C9 gene variations, the interference with the VKA metabolism is modified by PPI co-medication and the VCKORC1 genotype. Preceding knowledge of the genetic profile and the awareness for potentially occurring severe over-anticoagulation problems under PPI co-medication could contribute to a safer and personalized VKA pharmacotherapy.
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brunner-Ziegler
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
authors.forename: Dominic
authors.initials: D
authors.lastname: Magirr
authors.forename: Raute
authors.initials: R
authors.lastname: Sunder-Plassmann
authors.forename: Georgiana-Aura
authors.initials: GA
authors.lastname: Giurgea
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hammer
authors.forename: Christian
authors.initials: C
authors.lastname: Margeta
authors.forename: Martin
authors.initials: M
authors.lastname: Brunner
authors.forename: Renate
authors.initials: R
authors.lastname: Koppensteiner
authors.forename: Christine
authors.initials: C
authors.lastname: Mannhalter
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D013927:Thrombosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D064417:Vitamin K Epoxide Reductases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D054328:Proton Pump Inhibitors; D014812:Vitamin K; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: CYP2C9 protein; drug interactions; oral anticoagulant drugs; proton pump inhibitors; vitamin K epoxidase