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For centuries the South Pacific islanders have consumed kava (Piper methysticum) as a ceremonial intoxicating beverage. More recently, caplets of kava extracts have been commercialized for their anxiolytic and antidepressant activities. Several cases of hepatotoxicity have been reported following consumption of the commercial preparation whereas no serious health effects had been documented for the traditional beverage. A detailed comparison of commercial kava extracts (prepared in acetone, ethanol or methanol) and traditional kava (aqueous) reveals significant differences in the ratio of the major kavalactones. To show that these variations could lead to differences in biological activity, the extracts were compared for their inhibition of the major drug metabolizing P450 enzymes. In all cases (CYP3A4, CYP1A2, CYP2C9, and CYP2C19), the inhibition was more pronounced for the commercial preparation. Our results suggest that the variations in health effects reported for the kava extracts may result from the different preparation protocols used.

The Ginkgo biloba extract EGb761 was tested for its ability to inhibit the major human cytochrome P450 enzymes (CYPs). The full extract was found to strongly inhibit CYP2C9 (Ki = 14+/- 4 microg/mL), and to a lesser extent, CYP1A2 (Ki = 106 +/- 24 microg/mL), CYP2E1 (Ki = 127 +/- 42 microg/mL), and CYP3A4 (Ki = 155 +/- 43 microg/mL). The terpenoidic and flavonoidic fractions of the extract were tested separately against the same P450s to identify the source of inhibition by EGb761. The terpenoidic fraction inhibited only CYP2C9 (Ki = 15 +/-6 microg/mL) whereas the flavonoidic fraction of EGb761 showed high inhibition of CYP2C9, CYP1A2, CYP2E1, and CYP3A4 (Ki's between 4.9 and 55 microg/mL). The flavonoidic fraction was further fractionated using extraction and chromatography. Inhibition studies indicated that the majority of these fractions inhibited P450s at a significant level (IC50 < 40 microg/mL).

Nicotinic acid has been used as a cholesterol-lowering agent for a few decades already, whereas the cytoprotective and antiviral properties of nicotinamide are slowly gaining attention. In both cases however, very high doses are needed to achieve a therapeutic effect, resulting in blood concentrations sometimes as high as 15 mM. Based on their common pyridine functionality, we hypothesized that these two molecules could inhibit human P450 enzymes. In vitro inhibition studies demonstrate that, at their therapeutic concentrations, both nicotinic acid and nicotinamide inhibit CYP2D6 (Ki = 3.8 +/- 0.3 and 19 +/- 4 mM, respectively). Nicotinamide also inhibits CYP3A4 (Ki = 13 +/- 3 mM) and CYP2E1 (Ki = 13 +/- 8 mM). As expected for nitrogen-containing heteroaromatic molecules, spectrophotometric analysis indicates that the inhibition occurs via coordination of the pyridine nitrogen atom to the heme iron.