Pharmacokinetic interactions of a hop dietary supplement with drug metabolism in peri-menopausal and post-menopausal women

Botanical dietary supplements produced from hops (Humulus lupulus ) containing the chemopreventive compound xanthohumol and phytoestrogen 8-prenylnaringenin are used by women to manage menopausal symptoms. Due to the long half-lives of prenylated hop phenols and reports that they inhibit certain cytochrome P450 enzymes, a botanically authenticated and chemically standardized hop extract was tested for Phase I pharmacokinetic drug interactions. Sixteen peri- and post-menopausal women consumed the hop extract twice daily for 2 weeks, and the pharmacokinetics of tolbutamide, caffeine, dextromethorphan, and alprazolam were evaluated before and after supplementation as probe substrates for the enzymes CYP2C9, CYP1A2, CYP2D6, and CYP3A4/5, respectively. The observed area under the time-concentration curves were unaffected, except for alprazolam which decreased 7.6% (564.6 ± 46.1 h*μg/L pre-hop and 521.9 ± 36.1 h*μg/L post-hop; p -value 0.047), suggesting minor induction of CYP3A4/5. No enzyme inhibition was detected. According to FDA guidelines, this hop dietary supplement caused no clinically relevant pharmacokinetic interactions with respect to CYP2C9, CYP1A2 , CYP2D6, or CYP3A4/5. Serum obtained after consumption of the hop extract was analyzed using UHPLC-MS/MS to confirm compliance. Abundant Phase II conjugates of the hop prenylated phenols were observed including monoglucuronides and monosulfates as well as previously unreported diglucuronides and sulfate-glucuronic acid diconjugates.