Pharmacokinetics of prenylated hop phenols in women following oral administration of a standardized extract of hops

Abstract

Scope: Women seeking alternatives to hormone-replacement therapy for menopausal symptoms often try botanical dietary supplements containing extracts of hops (Humulus lupulus L.). Hops contain 8-prenylnaringenin (8-PN), a potent phytoestrogen, the related flavanones 6-prenylnaringenin and isoxanthohumol (IX), and the prenylated chalcone xanthohumol (XN).

Methods and results: After chemically and biologically standardizing an extract of spent hops to these marker compounds, an escalating dose study was carried out in menopausal women to evaluate safety and pharmacokinetics. 8-PN, 6-prenylnaringenin, IX, and XN, sex hormones, and prothrombin time were determined in blood samples and/or 24 h urine samples. There was no effect on sex hormones or blood clotting. The maximum serum concentrations of the prenylated phenols were dose-dependent and were reached from 2 to 7 h, indicating slow absorption. The marker compounds formed glucuronides that were found in serum and urine. Secondary peaks at 5 h in the serum concentration-time curves indicated enterohepatic recirculation. The serum concentration-time curves indicated demethylation of IX to form 8-PN and cyclization of XN to IX. Slow absorption and enterohepatic recirculation contributed to half-lives exceeding 20 h.

Conclusion: This human study indicated long half-lives of the estrogenic and proestrogenic prenylated phenols in hops but no acute toxicity.

Keywords: 8-Prenylnaringenin; Hops; Isoxanthohumol; Pharmacokinetics; Xanthohumol.

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figures

Figure 1

Chemical structures of prenylated hop phenols with estrogenic and/or proestrogenic activities.

Figure 2

Negative ion electrospray UHPLC-MS/MS with selected reaction monitoring (SRM) chromatograms of prenylated hop phenols in human urine from a single subject obtained A) before enzymatic deconjugation; and B) after deconjugation using β-glucuronidase and sulfatase. Note the large increase in the levels of prenyl phenols after enzymatic deconjugation, indicating that conjugates (especially glucuronides) were the major circulating forms of these compounds.

Figure 3

Negative ion electrospray UHPLC-MS-MS SRM chromatograms of prenylated hop phenols in human serum from the same subject as in Figure 2, A) before enzymatic deconjugation; and B) after deconjugation using β-glucuronidase and sulfatase.

Figure 4

Serum concentration-time curves of the 4 major prenylated hop phenols following oral administration of single doses of an extract of spent hops to 5 women. The curves represent total content of each compound (free + aglycon following enzymatic deconjugation) and were obtained by averaging concentrations from all 5 subjects. Secondary peaks occurring approximately 5-6 h post-dose suggest enterohepatic recirculation.