Abstract
Polypodium leucotomos（PL）is a fern native to Latin America, and its extract is used as an oral sunscreen; however, its safety during use has not been adequately investigated. Therefore, the aim of this study was to evaluate food-drug interactions associated with PL extract mediated by cytochrome P450 3A（CYP3A）inhibition and induction. Inhibition of CYP3A-mediated midazolam（MDZ）1’-hydroxylation activity by PL extract and its major phenolic components was evaluated in vitro using pooled human liver microsomes. In addition, MDZ pharmacokinetics were investigated in rats after a single dose, as well as after 1 week treatment with PL extract（30mg/kg）in order to evaluate the inhibitory and inducible effects of PL on CYP3A in vivo, respectively. Serum MDZ concentrations were analyzed and pharmacokinetic parameters were compared between PL- and water（control）-treated groups. In vitro, PL extract decreased MDZ 1’-hydroxylation activity in a concentration-dependent manner. However, the major phenolic compounds in PL extracts, namely caffeic, chlorogenic, p-coumaric, ferulic, and vanillic acids, did not exhibit any marked inhibitory effects on MDZ 1’-hydroxylation activity. In vivo, administration of a single dose of PL extract to rats significantly increased the area under the serum concentration-time curve from time 0 to infinity（AUC0–∞）and the maximum serum concentration（Cmax）of MDZ（by 57％ and 88％, respectively; P＜0.05）. In contrast, there were no significant changes in MDZ pharmacokinetic parameters after 1 week of treatment with PL extract. These results suggest that PL extract can cause a food-drug interaction by inhibiting CYP3A.
