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.

Keywords: botanical dietary supplements; clinical trial; drug interactions; hops; pharmacokinetics.

Conflict of interest statement

Conflict of Interest/Disclosure

The authors have no conflicts of interest to disclose.

Figures

Figure 1.

Structures and major fragment ions of the hop constituents xanthohumol, isoxanthohumol, 8-prenylnaringenin, and 6-prenylnaringenin. Confirmed using negative ion electrospray high resolution tandem mass spectrometry with collision-induced dissociation, these fragment ions were used for structure confirmation as well as for quantitative analysis during UHPLC-MS/MS with selected reaction monitoring.

Figure 2.

Average concentration-time curves for each probe substrate (16 participants). (Day 0/Day 22 = before/after intervention with hop botanical dietary supplement). Error bars denote ±SE.

Figure 3.

Comparison of individual areas under the curve (AUC) for each probe substrate before (day 0) and after (day 22) consuming a hop dietary supplement for 2 weeks.

Figure 4.

Negative ion electrospray UHPLC-MS high resolution mass chromatograms of the deprotonated hop constituents isoxanthohumol (IX), xanthohumol (XN), 8-prenylnaringenin (8-PN), and 6-prenylnaringenin (6-PN) in A) the hop supplement used in this study; and B) deconjugated serum from one participant after consuming the hop supplement for 2-weeks.

Figure 5.

Negative ion electrospray UHPLC-MS high resolution mass chromatograms of the deprotonated molecules of Phase II metabolites of hop constituents in human serum from one participant after consuming the hop dietary supplement for 2 weeks. Solid lines: conjugates of IX and XN; dashed lines: conjugates of 6-PN and 8-PN.