warfarin/phenylbutazone case

Case History 1
Warfarin - Phenylbutazone

Case Report: A 58 year-old male with coronary artery disease had received long-term treatment with warfarin for several years. The maintenance dose of warfarin was 8 mg/day. Arthritic manifestations developed in the dorsal spine, and after failing to respond to other agents the patient was given 200 mg of phenylbutazone daily. On the eleventh day of phenylbutazone treatment melena developed, while by day fourteen ecchymoses appeared on the trunk, and oral and pharyngeal hemorrhages occurred. At this time his prothrombin time was 50 seconds. The patient recovered after treatment with vitamin K and transfusions.

Experiment 1: A healthy 23 year-old male weighing 63 kg was given a single standard dose of warfarin, 1.5 mg/kg of body weight, orally. Venous blood samples were withdrawn and prothrombin time was determined at the indicated times. Two weeks later the subject was given phenylbutazone, 600 mg/day, by mouth for twenty-five days. On the fourteenth day he received that single standard dose of warfarin again and the prothrombin time was determined. The results are presented in Figure 1.

Experiment 2: Purified human serum albumin was dissolved in 100 mM potassium phosphate buffer, pH 7.4, at a concentration of 1%. Equilibrium dialysis was used to quantify the extent of binding of ¹⁴C-warfarin to albumin in the presence and absence of phenylbutazone. Radioactivity on both sides of the dialysis membrane was determined by counting a portion of the medium in a scintillation counter. Preliminary experiments demonstrated that there was no binding of warfarin to the dialysis membrane. The result are shown in Figure 2.

Experiment 3: A healthy 25 year-old male weighing 88 Kg was the subject for this study. Blood samples and complete 24 hour urine collection were made. Following two days of control sampling, a loading dose of 30 mg warfarin was administered orally along with 10 mg of vitamin K. Subsequently 10 mg of warfarin and 10 mg of vitamin K were administered daily on an empty stomach. Beginning with the twelfth day of warfarin administration, 100 mg of phenylbutazone was given orally three times a day. On day 22 of the study, phenylbutazone was discontinued while warfarin and vitamin K were continued. On day 32 of the study, warfarin was discontinued. Blood and urine samples were collected for one more week. The results obtained as shown in Figures 3 and 4.

Students should approach the case with the following questions in mind.

What conclusions can be drawn from each of the experiments?
Why was experiment 3 necessary?
What explanation(s) accounts for the observations made in the case history?

Figure 1. The effect of administration of pheylbutazone on the prothrombin time in a subject pretreated with warfarin.

Figure 2. The effects of phenylbutazone on the binding of warfarin to human serum albumin. The concentration of phenylbutazone in all experiments was 33 mM.

Figure 3. Temporal changes in total and unbound plasma concentrations of warfarin and total plasma phenylbutazone levels.

Figure 4. Plasma concentrations and daily rate of urinary excretion of 7-hydroxywarfarin.