Interaction between warfarin and functional foods derived from Bacillus subtilis natto

 Thrombotic diseases have been increasing recently and are said to account for approximately 30% of all causes of death among Japanese people. Potassium warfarin (hereinafter referred to as "wf'), a preventive for thrombosis, is the most commonly used oral coumarin anticoagulant and is known to have a number of interactions with foods and other drugs. For example, patients receiving wf must pay attention to the intake of foods and drugs containing vitamin K (hereinafter referred to as "vit K"), because vit K in large doses may cancel the effectiveness of wf.

 The anticoagulant effect of wf consists of negative action on the carboxylation of vit K and inhibition of the biosynthesis of the vit K-dependent blood coagulation factors in the liver. Drugs containing vit K include, in addition to vit K preparations, enteric nutrients, high-calorie transvenous nutritional infusions and menatetrenone—which is an anti-osteoporosis drug—and unless these drugs are administered, vit K is not delivered in drug form. However, vit K is contained in certain foods in large quantities, especially in natto which contains about 1 mg of vit K2 per 100 g).
Natto, a traditional Japanese food, has been eaten from old times for the purpose of maintaining good health as it is a good source of B-complex vitamins. In addition, proteases and glycolytic enzymes produced by Bacillus subtilis natto have been found to have a variety of bioactivities (2-4). According to a national survey of natto consumption conducted in 2003 over the Internet, people who eat natto everyday accounted for 14.6% of respondents while those who have one or more servings of natto every two to three days accounted for 47.0%. The number of servings had also increased in 32.3% of respondents and the reasons cited included nutritional value and health benefits (5). While natto has thus been routinely consumed, patients taking wf are instructed to avoid the intake of natto to prevent interactions with vit K (1-6).

Meanwhile, health foods have been flooding the market due to the health boom. A survey conducted among people 20 years of age or over showed that those with a history of consuming some type of health food accounted for 76% of respondents(7). It is therefore possible that patients taking wf are consuming health foods, and as health foods high in vit K have been reported to inhibit the effect of wf, this is resulting in the aggravation of conditions (8). Patients taking wf must accordingly pay close attention to the use of health foods. Health foods containing vit K in relatively large quantities include "nattokinase", "chlorella" and "green juice". It is important to identify the vit K content in health foods by checking ingredient labels to consider interactions with wf (1,6,9).

NKCP® is one of the health foods produced from the culture of B. subtilis natto. NKCP® has anticoagulant and thrombolytic effects on human blood and has demonstrated a significant shortening of the euglobulinlysis time and improvement of neck stiffness after ingestion in clinical studies (4,11). However, some patients taking wf have had concerns about interactions and chemists filling prescriptions have had difficulties determining whether they should recommend the taking of NKCP® as it is derived from B. subtilis natto. To help resolve these concerns, a quantitative determination of vit K2 in NKCP® was performed, as follows.