Usefulness of coadministration of bucolome in warfarin therapy: pharmacokinetic and pharmacodynamic analysis using outpatient prescriptions

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Abstract

Bucolome, a nonsteroidal anti-inflammatory drug, has often been coadministered to patients who take warfarin as an anticoagulant. This combination increases the anticoagulant effect, which is most likely due to the interaction of bucolome with the pharmacokinetics (PK) or pharmacodynamics (PD) of warfarin. More than 30 years ago the mechanism of this interaction was reported to be inhibition of warfarin protein binding by bucolome, and the inhibition of warfarin metabolism by bucolome was also recently reported. Here, we examined daily doses of warfarin and its anticoagulant effect (thrombo-test, TT) in outpatient prescriptions in five hospitals to elucidate the drug interaction and the usefulness of this drug combination. Among the warfarin prescriptions, 78 were for patients also taking bucolome and 99 were for patients not taking bucolome. The daily dose of warfarin in patients taking bucolome was significantly lower than those without bucolome (ca. 40%). TT in patients taking bucolome was significantly lower as compared to those not taking bucolome. Control of the anticoagulant effect was greater with coadministration of bucolome and warfarin than with warfarin alone. PK and PD analysis of our results suggests that the improved therapeutic effect resulting from coadministration of warfarin with bucolome was due to lower and less patient-to-patient variation of intrinsic hepatic clearance (CLint) of warfarin, since bucolome decreased the high CLint but did not have a great effect on the low CLint. In conclusion, administration of bucolome in warfarin therapy is useful to control the anticoagulant effect of warfarin. Attention should also be paid to the enzymatic inhibition by bucolome on the PK of coadministered drugs.

Introduction

Warfarin has been used all over the world for decades for prevention and treatment of thrombus and embolism as an anticoagulant, and it is still an essential drug today. Warfarin, however, interacts with many other drugs (Koch-Weser and Sellers, 1971, MacLeod and Sellers, 1976, Deykin, 1970), so the optimization of dosage regimen is very difficult. Then, thrombo-test (TT) is generally used in Japan in the warfarin therapy, since TT values was found to be more useful than prothrombin time to control the anticoagulant activity during warfarin therapy in patients (Ikuma et al., 1999, Numata et al., 2001).

Bucolome has often been coadministered to patients who take warfarin. The coadministration ratio of warfarin and bucolome is extremely high in Niigata prefecture (ca. 300 km north from Tokyo, border on the Japan Sea) compared to other region and prefectures in Japan. Bucolome is a nonsteroidal anti-inflammatory drug. It is used for remission of inflammation and tumefaction after surgical operation and external injury. It is also applied for anti-inflammation, analgesic and antipyretic in rheumatoid arthritis, arthrosis deformans, cystitis, erythema exsudativum multiforme, acute sinusitis, acute otitis media and uterus adnexitis. Bucolome also decreases plasma uricate (uric acid) level in gout patients. Although application of bucolome should be limited to these uses, it is often administered to patients during warfarin therapy. Most of the patients who take warfarin in Niigata take bucolome, whereas those in the other areas do not. Therefore, patients who move in or out of Niigata may have trouble in their dosage regimen of warfarin.

Adequate information is found in the drug information sheets both in warfarin and bucolome preparations. Deliberate coadministration of bucolome with warfarin was reported to reduce the warfarin dose, and a steady therapeutic effect of warfarin was obtained. For example, Matsuoka (1977) reported that TT was maintained at about 15% when bucolome (300–600 mg/day) was used together with warfarin (1.0–1.5 mg/day). Sakashita et al. (1978) reported the usefulness of coadministration of bucolome in warfarin therapy in patients who had undergone operation to have an artificial valve placed in the heart. Sakuragawa et al. (1982) reported easier control of anticoagulant activity (TT = 10–25%) of warfarin at a daily dose of 1–2 mg/day with coadministration of bucolome (300 mg/day) than warfarin therapy without bucolome in similar patients. The mechanism by which bucolome increases the warfarin effect is interesting. Matsuoka (1977) reported that albumin-unbound warfarin in plasma was increased by coadministration of bucolome, which has a higher affinity to plasma albumin. In addition, Majima et al. (1982) found that protein binding of warfarin was decreased by bucolome. While these two explanations differ, they both indicate that the interaction between warfarin and bucolome is related to protein binding. On the other hand, Takahashi et al. (1999) noted that inhibition by bucolome of 7-oxidation on cytochrome P-450 (CYP) 2C9 to (S)-warfarin, which shows a higher pharmacological effect than (R)-warfarin, was important, in addition to the interaction related to protein binding.

We therefore examined daily doses of warfarin and its anticoagulant effect (TT) from outpatient prescriptions in five hospitals in different parts of Japan (Niigata, Toyama and Saitama prefectures) to elucidate the drug interaction and the mechanism of this drug combination. Usefulness and risk of the combination of bucolome with warfarin were evaluated by pharmacokinetic (PK) and pharmacodynamic (PD) analysis of warfarin.

Section snippets

PK of warfarin

Because the biological half-life of warfarin is very long (Holford, 1986), orally repeated administration of the drug shows small peaks and troughs in the time course of plasma level. Since warfarin is eliminated mostly by liver metabolism (Banfield et al., 1983), the total body clearance of the drug is similar to hepatic clearance. In addition, the liver extraction rate of warfarin is too low to be classified as a low extraction drug. The fraction of warfarin that permeates through the

Survey of prescriptions and TT values

Patients with prescriptions for warfarin were selected from outpatients in five hospitals, as shown in Table 1. Number of patients is 177. Their ages were in the range of 42–86 (mean ± S.D.: 68 ± 11), and 70% were male among them. Most patients had basal diseases such as ischemic heart disease, valvular disease, arteriosclerosis obliterans, and they had complications of heart failure, hypertension, diabetes, hyperlipemia and so on.

The daily dose of warfarin, coadministration of bucolome, and other

Results

Fig. 1 shows a histogram of the daily dose of patients taking warfarin alone or warfarin and bucolome (78 and 99 patients, respectively). The daily dose of warfarin in patients who also took bucolome was about 40% of those who did not take bucolome, and the dose was significantly lower than the dose without bucolome (p < 0.05). Fig. 2 shows a histogram of TT values. The therapeutic range of TT values (about 8–15%) was obtained in about 50% patients by coadministration of bucolome, whereas TT

Discussion

The present calculation of CLint of warfarin suggests that the interaction between warfarin and bucolome was caused by inhibition of metabolic reaction to warfarin by bucolome. Therefore, sufficient efficacy of warfarin with coadministration of bucolome was obtained even with a low dose of warfarin by its high protein-unbound level. In addition, the difference between peak and trough levels of warfarin became smaller because of an increase in biological half-life. Therefore, the time-dependent

Acknowledgement

The authors are very grateful to Mr. Shuji Ito of Josai University for his assistance in examining the warfarin data in patients.

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