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Clinical Specialist in Neurology Department of Neurology and Institute of Neurological Sciences & Psychiatry Faculty of Medicine Hacettepe University Ankara, Turkey
Specialist in Pharmacology Department of Pharmacology Faculty of Medicine Hacettepe University
Professor of Neurology Department of Neurology Faculty of Medicine Hacettepe University
Professor of Pharmacology Department of Pharmacology Faculty of Medicine Hacettepe University
Clinical Pharmacologist Department of Pharmacology Faculty of
Medicine Hacettepe University 06100 S
hhiye Ankara, Turkey fax 90 312
3105312
uyasar{at}hacettepe.edu.tr
Published Online, March 23, 2004. www.theannals.com, DOI 10.1345/aph.1D450
Case Report. A 44-year-old Turkish woman was admitted to the hospital due to transient loss of vision. Medical history was remarkable for headache, hypertension, and epilepsy. She was diagnosed with antiphospholipid antibody syndrome. Her base-line international normalized ratio (INR) was 1.08. Warfarin was started in July 2002 at a dose of 5 mg/day and was gradually increased to 15 mg/day until INR values reached the desired level of 2.5–3 within 10 months (Table 1). Initial concomitant therapy included verapamil 120 mg/day and barbexaclone 100 mg/day. Barbexaclone was gradually withdrawn in August 2002 and replaced with gabapentin 900 mg/day. She was not on a special diet and did not receive vitamin supplements regularly.
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We determined the CYP2C9 enzyme activity using a single oral 25-mg dose of losartan as a probe drug3 in August 2003. The ratio of losartan to E-3174 in the patient's urine was 3.2, which is threefold higher than the population mean for the CYP2C9*1*1 genotype.3 This value suggests quite low activity of CYP2C9 in this patient. The patient's genotype was determined as CYP2C9*1*2 by using a polymerase-chain reaction–based endonuclease digestion method.1 Written informed consent was obtained from the subject for the phenotyping and genotyping procedure.
Discussion. Our patient's anticoagulant treatment with warfarin was compounded by the persistence of a low INR. As warfarin is a substrate for CYP2C9, low enzyme activity would result in slow inactivation of warfarin. However, contrary to expectations, the present case had low activity of CYP2C9, but still required high doses of warfarin.
It has been reported that other factors, such as drug interactions, vitamin K dietary intake, and abnormalities in vitamin K epoxide reductase can also affect anticoagulation with warfarin.2,4 The patient's daily vitamin K intake seemed to be appropriate. However, this does not rule out any abnormalities in vitamin K epoxide reductase in the patient. Another possible reason for warfarin resistance in this patient could be the concomitant use of barbexaclone, a phenobarbital-like drug that is known to induce CYP2C9. However, warfarin doses had to be increased even after the withdrawal of barbexaclone.
In this patient, analysis of concentrations of S-warfarin and 7-hydroxy-warfarin, a major metabolite of S-warfarin primarily produced by CYP2C9, would give more valuable information; however, we used losartan as a probe to measure real-time CYP2C9 activity. Although CYP2C9 is important for the metabolism of warfarin,2 our case supports the view that CYP2C9 genotyping and phenotyping may not have a predictive value in every subject.4,5
References
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