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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 CYP3A4‐mediated 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 ± 3.65 ng h/ml, maximum serum concentration was 7.81 ± 1.25 ng/ml, and half‐life was 2.32 ± 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 ± 2.97 ng h/ml, maximum serum concentration: 8.78 ± 1.67 ng/ml, half‐life: 2.52 ± 0.52 h). Therefore, short‐term oral administration of P. leucotomos extract did not cause food‐drug interactions mediated by CYP3A4 inhibition in humans. [ABSTRACT FROM AUTHOR]

Aim: Wood creosote (WC), an over‐the‐counter (OTC) drug, has been used as an anti‐diarrheal agent for many years; however, its safety in combination with other drugs has not been adequately investigated. The current study was conducted to evaluate whether WC may cause drug interactions through the inhibition of cytochrome P450 (CYP). Methods: The inhibitory effects of WC on ethoxyresorufin O‐deethylation, paclitaxel 6α‐hydroxylation, S‐warfarin 7‐hydroxylation, S‐mephenytoin 4′‐hydroxylation, bufuralol1′‐hydroxylation, and midazolam (MDZ) 1′‐hydroxylation were investigated using human liver microsomes as the marker activities for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. In addition, the effects of single and three‐day multiple treatments of WC (30 mg/kg) on CYP2C‐mediated tolbutamide (TB, 20 mg/kg) and CYP3A‐mediated MDZ (15 mg/kg) metabolism were investigated in rats in vivo. Results: WC at clinical doses did not show a considerable inhibitory effect on any of the CYP activities examined in the in vitro study. CYP2C9 and CYP2C19 activities were inhibited by high concentrations of the WC (100 μg/mL); however, the IC50 values were approximately 70 times higher than the reported circulating levels of the main ingredients in WC. Furthermore, there were no marked changes in the pharmacokinetic parameters of TB and MDZ (area under the serum concentration–time curve, maximum serum concentrations, and elimination half‐life) after single or three‐day multiple treatments with WC. Conclusion: These results suggest that clinical doses of WC are unlikely to cause drug interactions mediated by the inhibition of CYPs. [ABSTRACT FROM AUTHOR]