Inhibitory Effect of <i>Polypodium Leucotomos</i> Extract on Cytochrome P450 3A-mediated Midazolam Metabolism

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 fooddrug 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 30 mg / 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 signi cantly increased the area under the serum concentration-time curve from time 0 to infinity AUC 0-and the maximum serum concentration C max of MDZ by 57 and 88 , respectively ; P 0.05. In contrast, there were no signi cant 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.

Short‐term administration of Polypodium leucotomos extract does not inhibit CYP3A4‐mediated metabolism of midazolam in healthy subjects: an open‐label, two‐period, fixed‐sequence study

“…Based on the findings of previous in vitro studies, the results of this study were unexpected. We previously reported that the PL extract competitively inhibits midazolam metabolism in human liver microsomes, 11 and predicted a similar effect in vivo.…”

“…Previously, we reported that 1-week treatment with PL extract results in no significant changes in the pharmacokinetics of midazolam in rats. 11 However, in the subsequent studies, the expression of CYP3A9 mRNA in the small intestine was found to be significantly increased (59%) by PL extract treatment, indicating the induction and/or activation of small intestinal CYP3A9 in rats (Nishimura, Y., unpublished data). As CYP3A4 is involved in the metabolism of many drugs, long-term use of the PL extract would increase the opportunities for its concomitant use with drugs that are metabolized by this enzyme.…”

“…[16][17][18] However, our previous in vitro studies have shown that these phenolic acids do not inhibit the CYP3A4 activity in human liver microsomes. 11 The CYP3A4-inhibitory components in PL extract have not yet been identified, and their properties and pharmacokinetic characteristics after oral administration remain unclear. In this study, PL extract was administered three times (in the morning and at noon the day before, and in the morning of the day of midazolam administration), to investigate its inhibitory effect on midazolam metabolism when sufficient quantities of the extract were present in the body.…”

“…In a previous study, we investigated CYP3A4‐mediated FDIs that may be caused by PL extract. In vitro studies using human liver microsomes have shown that PL extract competitively inhibits the CYP3A4‐catalyzed 1′‐hydroxylation of midazolam 11 . Furthermore, the administration of a single oral dose of PL extract in rats results in a 1.6‐fold increase in the area under the concentration‐time curve (AUC) and a 1.9‐fold increase in the maximum serum concentration (C max ) of midazolam, indicating that this extract leads to drug interactions via the inhibition of CYP3A isoforms.…”

Drug interactions of natural supplements in dermatology: a review

“…As described above, IBM Micromedex generated no results for drug–drug interactions, and most reviews addressing polypodium leucotomos’ safety profile did not describe drug interactions 22 . A study in animal models observed P450 CYP3A inhibition by polypodium leucotomos in mice dosed with midazolam 23 . This may warrant caution in patients using CYP3A metabolized drugs with narrow therapeutic indexes, including tacrolimus, the drug levels of which are especially important to maintain in transplant patients 24 .…”