Kaempferia parviflora (KP) extract has recently attracted attention in Japan as a dietary supplement; however, there is little information regarding food-drug interactions (FDIs). The current study was conducted to clarify the FDI of KP extract via inhibition of cytochrome P450 3A (CYP3A), a typical drug-metabolizing enzyme. The inhibitory effects of KP extract and its main ingredients, 5,7-dimethoxyflavone (5,7-DMF) and 3,5,7,3’,4’-pentamethoxyflavone (3,5,7,3’,4’-PMF), on CYP3A-mediated midazolam 1’-hydroxylation (MDZ 1’-OH) activity were investigated in human liver microsomes. In addition, the effect of a single oral treatment with KP extract (135 mg/kg) on oral MDZ (15 mg/kg) metabolism was investigated in rats. Serum MDZ concentration was analyzed and pharmacokinetic parameters were compared with the control group. KP extract competitively inhibited MDZ 1’-OH activity with an inhibition constant value of 78.14 µg/ml, which was lower than the estimated concentration in the small intestine after ingestion. Furthermore, KP extract, 5,7-DMF, and 3,5,7,3’,4’-PMF inhibited the activity in a time-, NADPH-, and concentration-dependent manner. In vivo study showed that administration of KP extract to rats 2 h before MDZ significantly increased the area under the serum concentration-time curve and the maximum concentration of MDZ significantly by 2.3- and 1.9- fold, respectively ( p < 0.05). Conversely, administration of MDZ 18 h after KP extract treatment displayed a weaker effect. These results suggest that KP extract competitively inhibits CYP3A-mediated MDZ metabolism, and that this inhibition may be time-dependent but not irreversible. This work suggests an FDI through CYP3A inhibition by KP extract.

The extract of Polypodium leucotomos is used as a dietary supplement for its ultraviolet radiation-protective properties. Polypodium leucotomos extract reportedly inhibits CYP3A, which is important for drug metabolism in vitro in human microsomes and in vivo in rats.In this study, we explored the inhibitory effect of the P. leucotomos extract on CYP3A4mediated midazolam metabolism in humans. This open-label, two-period, fixed-sequence study was performed on six healthy, Japanese, male volunteers. During period 1 (control), midazolam (1 mg) was orally administered. After a wash-out period of at least 5 days, period 2 was initiated. Subjects ingested P. leucotomos extract (240 mg) once in the morning and once at noon on the day before midazolam administration, and once the next morning (thrice overall). Midazolam was administered as in period 1. Blood samples were regularly collected for 8 hours after drug administration, and serum midazolam concentration was determined by ultra-fast liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters of midazolam were calculated and compared between the two periods. The area under the concentration-time curve was 19.18 AE 3.65 ng h/ml, maximum serum concentration was 7.81 AE 1.25 ng/ml, and half-life was 2.32 AE 0.35 hours during period 2. These parameters did not differ from those recorded in period 1 (area under the concentration-time curve: 18.74 AE 2.97 ng h/ml, maximum serum concentration: 8.78 AE 1.67 ng/ml, half-life: 2.52 AE 0.52 h). Therefore, short-term oral administration of P. leucotomos extract did not cause food-drug interactions mediated by CYP3A4 inhibition in humans.