CYP2C9 Mutation Affecting the Individual Variability of Warfarin Dose Requirement
A 77-year-old female patient with the main complaint of gait disturbance was transferred to the Department of Rehabilitation Medicine. The patient had been diagnosed with colorectal cancer 6 years ago and received right Hemicolectomy and Total Hip Replacement Arthroplasty due to the metastasis of cancer to her right hip joint, two days before. In an ultrasonography on her leg veins, as an examination carried out two days before the surgery, a blood clot on the posterior tibial vein and thromboembolism on the right upper lobe, in addition to mesenchyma on the left inferior lobe from a chest CT were observed. As such, an anticoagulation treatment of thrombotic lesion was started on the next day from the surgery. The patient, on the day of the transfer to the Department of Rehabilitation Medicine, was taking oxcodone (20 mg/day), atorvastatin (20 mg/day), gabapentin (900 mg/day), levosulpiride (25 mg/day), and cetamadol (R) (325 mg/37.5 mg), three times a day. Her weight was 57.6 kg and her height was 160 cm. There was no special opinion on the basic blood chemistry and electrolyte, and on the first blood coagulation test, PT was 14.2 seconds and INR was 1.10, which were normal.\nAs an anticoagulation treatment, the administration of warfarin started using enoxaparin (60 mg/day). The initial dose of warfarin was 8 mg after dinner on the first day, and PT next morning was 15.8 seconds and INR was measured 1.26. In the evening on the same day, 8 mg was administered again, and PT on the following morning was 62.6 seconds and INR was 7.33. In addition, the value of the coagulation remarkably increased. Thus, the authors, first considered the possibility of overdose of warfarin and an interaction with other drugs. The administration of cetamadol and warfarin was stopped, and Vitamin K 10 mg IV was administered to prevent copious bleeding, and then stopped the rehabilitation and radiation treatments. On the following morning, PT was reduced to 23.0 seconds and INR to 2.03, so warfarin was administered again for two days (2 mg/day), and the next morning's PT remarkably increased to 69.1 seconds and INR to 8.31. Again, Vitamin K 10 mg IV was administered, and the administration of warfarin was stopped. Four days after, INR was maintained at more than 4.0 and on the fifth day, PT was reduced to 20.8 and INR to 1.79. As a result, it turned out to be CYP2C9*1/*3 genotype, in which the heterozygous A1075C (Ile359Leu) polymorphism was found on the result of a CYP2C9 genotype analysis, in which a Polymerase Chain Reaction (PCR) and Direct Sequencing method were carried out, and an intermediate metabolizer with deteriorated activation of enzyme compared to that of a wild type person. It was found that VKORC1 genotype as 1173TT (homozygous) had a genetically high warfarin sensitivity. Thus, the authors started to find the maintained dose of warfarin of about 0.5-1 mg/day again, and with the dose of 0.5 mg/day, for the patient's value of coagulation, PT and INR was maintained at 21 seconds and about 1.9, respectively, and two weeks later, the radiation treatment was terminated. Consequently, the patient was discharged from the hospital with the proper function of independent walking, using a rolling walker.