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Cytochrome P450 polymorphisms, celecoxib, and warfarin

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Both warfarin and non-steroidal anti-inflammatory drugs are metabolised by cytochrome P450 (CYP2C9 enzyme). There are three variants of the CYP2C9 gene (CYP2C9*1, *2, and *3) and in European populations about 80% of people are homozygous for the CYP2C9*1 allele. The *2 and *3 alleles are found in 11% and 5–7% respectively. The *2 variant is associated with about 12% of the enzyme activity found with the *1 gene and the *3 variant with 5% of the activity. Carriers of the variant alleles need smaller doses of warfarin and the concomitant use of drugs that compete for CYP2C9 activity may further reduce warfarin metabolism and result in excessive anticoagulation. Such an occurrence has been described in a case report from New York.

An elderly woman began taking warfarin after having a pacemaker inserted and for a year had an international normalised ratio (INR) for prothrombin time of 2.2–2.6 on a dose of 2.5 mg daily. Within two weeks of taking celecoxib for joint pains the INR had increased to 3.5. The dose of warfarin was reduced to 1 mg daily but four weeks after starting celecoxib treatment she was admitted to hospital with widespread bleeding into the skin. Her haemoglobin concentration had fallen from 160 to 85 g/l over the past week and the INR was >10. She was also taking digoxin, ranitidine, and atorvastatin. On analysis of CYP2C9 genotype she was found to be heterozygous for both the *2 and the *3 alleles. She made a complete recovery after stopping both warfarin and celecoxib.

This patient, a heterozygote for both CYP2C9*2 and CYP2C9*3 was satisfactorily treated with a modest dose of warfarin but on adding celecoxib to her treatment her anticoagulation became excessive despite a reduction in dose of warfarin. It appears that celecoxib competed with warfarin for P450 enzyme activity which was already genetically low.

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