Allelic variants of cytochrome P450 2C9 modify the interaction between nonsteroidal anti-inflammatory drugs and coumarin anticoagulants.
BACKGROUND
Cytochrome P450 (CYP) plays a key role in the metabolism of coumarin anticoagulants and nonsteroidal anti-inflammatory drugs (NSAIDs). Because CYP2C9 is a genetically polymorphic enzyme, genetic variability could play an important role in the potential interaction between NSAIDs and coumarins. We investigated whether NSAIDs were associated with overanticoagulation during therapy with coumarins and evaluated the effect of the CYP2C9 polymorphisms on this potential interaction.


METHODS
We conducted a population-based cohort study among patients of an anticoagulation clinic who were treated with acenocoumarol or phenprocoumon between April 1, 1991, and May 31, 2003, and whose CYP2C9 status was known. Patients were followed up until an international normalized ratio (INR) of 6.0 or greater was reached or until the end of treatment, death, or the end of the study. Proportional hazards regression analysis was used to estimate the risk of an INR of 6.0 or greater in relation to concomitant use of a coumarin anticoagulant and NSAIDs after adjustment for several potentially confounding factors. To study effect modification by CYP2C9 genotype, stratified analyses were performed for wild-type patients and patients with a variant genotype.


RESULTS
Of the 973 patients in the cohort, 415 had an INR of 6.0 or greater. Several NSAIDs increased the risk of overanticoagulation. The risk of overanticoagulation was 2.98 (95% confidence interval, 1.09-7.02) in coumarin-treated patients taking NSAIDs with a CYP2C9*2 allele and 10.8 (95% confidence interval, 2.57-34.6) in those with a CYP2C9*3 allele.


CONCLUSIONS
Several NSAIDs were associated with overanticoagulation. For NSAIDs that are known CYP2C9 substrates, this risk was modified by allelic variants of CYP2C9. More frequent INR monitoring of patients taking NSAIDs is warranted.
Visser
Loes E
LE
Pharmacoepidemiology Unit, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
van Schaik
Ron H N
RH
van Vliet
Martin
M
Trienekens
Paul H
PH
De Smet
Peter A G M
PA
Vulto
Arnold G
AG
Hofman
Albert
A
van Duijn
Cornelia M
CM
Stricker
Bruno H Ch
BH
D000074:Acenocoumarol / Q000009:adverse effects / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000378:metabolism*; D000925:Anticoagulants / Q000009:adverse effects / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions / Q000235:genetics / Q000502:physiology; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010644:Phenprocoumon / Q000009:adverse effects / Q000378:metabolism*; D011110:Polymorphism, Genetic
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000074:Acenocoumarol; D010644:Phenprocoumon