Pharmacokinetic Interactions of a Hop Dietary Supplement with Drug Metabolism in Perimenopausal and Postmenopausal Women

Abstract

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. Because of 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 postmenopausal 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. The serum obtained after consumption of the hop extract was analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry 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.

No Clinically Relevant Pharmacokinetic Interactions of a Red Clover Dietary Supplement with Cytochrome P450 Enzymes in Women

“…Also, there was considerable variation between the subject in dextromethorphan metabolism due to inclusion of both intermediate and extensive metabolizing phenotypes for CYP2D6 (Figure ). Similar phenotype variations in dextromethorphan CYP2D6 pharmacokinetics have been reported previously …”

“…Participants were recruited and gave informed consent following the human participant protocol approved by the University of Illinois at Chicago Institutional Review Board (#2015-0651). Inclusion and exclusion criteria were as described in our previous publication . Briefly, perimenopausal and postmenopausal women were included between 40 and 79 years of age with a body mass index (BMI) ≤40 and in good health (based on physical examination including blood and urine screens).…”

“…Inclusion and exclusion criteria were as described in our previous publication. 17 Briefly, perimenopausal and postmenopausal women were included between 40 and 79 years of age with a body mass index (BMI) ≤40 and in good health (based on physical examination including blood and urine screens). Individuals were excluded if they had any chronic diseases or significant medical conditions; smoking; alcohol or drug abuse; known allergy or hypersensitivity to red clover or any probe substrates used in the study; positive pregnancy test; or hormone therapy within 8 (for oral agents) or 4 weeks (for transdermal or other topical agents).…”

“…The U.S. Food and Drug Administration has established guidelines for the clinical evaluation of drugs for potential drug interactions and recommends clinical evaluation when inhibition or induction is suspected for CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2. This approach has been extended to the evaluation of the interactions between CYP enzymes and botanical dietary supplements, including hops (Humulus lupulus L.), black cohosh (Actaea racemosa), echinacea (Echinacea purpurea), , gingko (Ginkgo biloba), milk thistle (Silybum marianum), and St. John’s wort (Hypericum perforatum L.) . The approach uses one or a cocktail of probe substrates, each of which is mainly metabolized by a single CYP enzyme.…”

Herb–Drug Interactions: Worlds Intersect with the Patient at the Center

“…The following are available online at , Table S1: Pharmacokinetic Pathways for Drugs Implicated in Herb–Drug Interactions Where Herb Was Clinically Studied; Table S2: Findings of Clinical Studies; Table S3: Comparison of Case Reports to Herb–Drug Interaction Checkers; Table S4: Case Report Summaries; Table S5: Materials and Methods of Clinical Studies. (References [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 …”