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Pharmacokinetics of Prenylated Hop Phenols in Menopausal Women
Date 10-31-2014
HC# 101451-507
Keywords:
Hops (Humulus lupulus)
Pharmacokinetics
Menopause

van Breemen RB, Yuan Y, Banuvar S, et al. Pharmacokinetics of prenylated hop phenols in women following oral administration of a standardized extract of hops. Mol Nutr Food Res. October 2014;58(10):1962-1969. doi: 10.1002/mnfr.201400245.

The female inflorescences of the hop (Humulus lupulus) plant, which are referred to as strobuli, cones, or simply hops, are used to treat menopausal hot flashes. The purpose of this dose-escalating study was to evaluate the safety of a hops extract and the pharmacokinetics of its bioactive prenylated phenols, the chalcone xanthohumol (XN) and the flavanones isoxanthohumol (IX), 6-prenylnaringenin (6-PN), and 8-prenylnaringenin (8-PN).

Healthy post-menopausal women (n = 5, aged 55-68 years) participated in this study conducted at the University of Illinois at Chicago and Northwestern University; Chicago, Illinois. Subjects stopped hormone replacement therapy (HRT) ≥ 2 months before this study. No beer consumption was permitted for 1 month before or during the study.

The female hops cone extract was prepared by Hopsteiner (New York, NY) from spent hops (the plant material remaining after the bitter acids and essential oils are extracted for use in the brewing industry). The spent hops extract was standardized biologically to estrogen-responsive alkaline phosphatase enzyme and standardized chemically to XN, IX, 6-PN, and 8-PN content.1 Each capsule contained 59.3 mg extract with 21.3 mg XN, 0.80 mg IX, 1.30 mg 6-PN, and 0.25 mg 8-PN.

One capsule (low dose) of the extract was taken for 5 days. After a 1-month washout period, 2 capsules (medium dose) were taken for 5 days. After another 1-month washout period, 3 capsules (high dose) were taken for 5 days. During each treatment cycle, urine was collected during the 24 hours after the first dose and blood samples were drawn hourly for the first 24 hours after the first dose and then 1x/day for the next 4 days. The blood serum and 24-h urine samples were assayed to determine the pharmacokinetics of the hop prenylated phenols XN, IX, 6-PN, and 8-PN. To assess acute toxicity of the hops extract, blood samples were tested to determine prothrombin time (PT) and the levels of estradiol, follicle-stimulating hormone, and luteinizing hormone.

At time zero, no prenylated phenols were detected in the serum or urine. Traces of unconjugated XN, IX, and 8-PN were detected in the 24-h urine, while only unconjugated IX and XN were detected in the serum with the medium and high doses.

The prenylated phenols were absorbed slowly into the bloodstream, and slowly eliminated over 24 hours. The peak serum concentrations were dose dependent. Over 98% of the urinary prenylated phenols were in the glucuronide form, and as the dose of the hop extract increased, the urinary excretion of each compound increased proportionally. However, urinary excretion of all 4 compounds was low (<2%), indicating other routes of elimination such as biliary secretion.   

There was a second peak in the serum concentration-time curves (AUC) at 5 hours post-dose for all 4 prenylated phenols, suggesting enterohepatic recirculation. The authors posit that the slow absorption and enterohepatic recirculation of the prenylated phenols could account for the long half-lives observed.

One of the subjects had much higher serum concentration of XN and IX at the medium and high doses compared to the other four subjects, as well as a 3-fold higher ratio of 8-PN/XN urinary excretion. The authors state that these findings indicate that "enzymatic polymorphisms as well as environmental factors such as microbiota variations can directly impact individual rates of conversion of IX to 8-PN."

There were no significant changes in estradiol, follicle-stimulating hormone, luteinizing hormone, or PT.

This is the first study to evaluate the pharmacokinetics of these 4 hop prenylated phenols in the matrix of a biologically and chemically standardized hops extract. The peak serum concentrations were dose-dependent and the mean time to reach the maximum concentration was relatively long. Glucuronides were predominant forms of these compounds found in the serum and urine, which underwent enterohepatic recirculation to extend their half-lives. In agreement with other studies, the pharmacokinetic data indicates that XN is recyclized in vivo to IX, and that the half life and total amount of the most estrogenic prenylated phenol, 8-PN, is increased by conversion of IX to 8-PN.

The authors conclude "that short-term consumption of a chemically and biologically standardized preparation of spent hops is safe for women and that once daily dosing might be appropriate." However, there were significant intra-individual differences just in this small (n=5) study population, and neither the gut flora nor the cytochrome P450 1A2 (CYP1A2) phenotypes of the subjects were characterized. These results should be viewed as preliminary, pending a larger study with a representative sampling of metabolically characterized subjects.


—Heather S. Oliff, PhD


References

1Krause E, Yuan Y, Hajirahimkhan A, et al. Biological and chemical standardization of a hop (Humulus lupulus) botanical dietary supplement. Biomed Chromatogr. June 2014;28(6):729-734.