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Influence of proton pump inhibitors and VKORC 1 mutations on CYP 2C9‐mediated dose requirements of vitamin K antagonist therapy: a pilot study
Author(s) -
BrunnerZiegler Sophie,
Jilma Bernd,
Magirr Dominic,
SunderPlassmann Raute,
Giurgea GeorgianaAura,
Hammer Alexandra,
Margeta Christian,
Brunner Martin,
Koppensteiner Renate,
Mannhalter Christine
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13082
Subject(s) - vkorc1 , cyp2c9 , genotype , context (archaeology) , pharmacology , vitamin k antagonist , medicine , warfarin , biology , cytochrome p450 , genetics , atrial fibrillation , gene , metabolism , paleontology
Summary 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 ( VKORC 1) and cytochrome P450 2C9 ( CYP 2C9), 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 PPI s in relation to the CYP 2C9 genotype. Median weekly stable VKA dose requirements over 1 year were recorded in 69 patients. Patients were genotyped for CYP 2C9 *2, CYP 2C9 *3, VKORC 1 c.‐1639G>A and VKORC 1 c.174‐136C>T and assessed for an association with PPI use and total VKA maintenance dose requirements. PPI users with CYP 2C9 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 CYP 2C9 genotype had no significant influence on oral VKA dose requirements. Further, the combined CYP 2C9 / VKORC 1 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 CYP 2C9 gene variations, the interference with the VKA metabolism is modified by PPI co‐medication and the VCKORC 1 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.