Bailey et al. demonstrated that the blood concentration of anti-hypertensive drugs such as nifedipine was kept at a high level with grapefruit juice co-administered to mask the taste of alcohol. Since that time there has been a great deal of interest in food–drug interactions because of the clinical risks associated with changes in the bioavailability or metabolic rate of clinically administered drugs. In spite of the increasing use of herbal remedies and nutraceuticals, information on the drug interaction that occurs with them including foodstuffs, is still insufficient to understand the clinical risks.
We have studied drug interactions with foodstuffs such as grapefruit juice and pepper, isolating several potent CYP3A4 inhibitors in each material. The fact that a foodstuff contains more than one inhibitor suggests that the clinical effect of drug interaction with herbs and foodstuffs could be better understood by studying the mixture of inhibitors and/or an extract of these.
During our study on CYP3A4 inhibitors contained in food, we found that the supplement of C. racemosa
exhibited potent inhibition. The polar fraction from the extract showed 44% inhibition at 5 mg/ml, which was as potent as the inhibition produced by ketoconazole, 58% at 5 µg/ml. We clarified the main constituents, cognate triterpene glycosides, as the CYP3A4 inhibitory principles. To date, highly potent CYP3A4 inhibitors in food have been reported, e.g. paradisins A and B (IC50
, 0.07 and 0.07 µM) from grapefruit juice (15
), dipiperamide A (IC50
, 0.18 µM) from white pepper (17
) and gomisin C (IC50
, 0.254 µM) from Schisandra fruit (29
). Although the IC50
value of each isolate was moderate, the high content of a series of cognates in the supplement could result in the exhibition of significant CYP inhibition. Care should be taken to avoid concomitant intake of black cohosh with any kind of medication because of the possibility of increasing the bioavailable concentration of drugs in the blood by the downregulation suppression of CYP3A4. Medical practitioners therefore should pay more attention in order to avoid any trouble with diet containing black cohosh.
The IC50, 0.027 mg/ml, of the extract of black cohosh was very low in spite of the weak activities of the isolated compounds. The IC50 value indicates that 40 mg of the black cohosh extract could be estimated to inhibit the metabolism of roughly half a dose of nifedipine for 1 day.
Evaluation of the IC50 of both constituents and the extract may be useful for clinical study of drug interactions of herbs and foodstuffs predicted to be a clinical risk, especially for the study of the mechanism of action and the pharmacokinetics.