Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women.
OBJECTIVE
Pre-clinical data suggest that the racemic phyto-oestrogen 8-prenylnaringenin (8-PN) may have beneficial effects in postmenopausal women and may become an alternative to classical hormone replacement therapy (HRT) treatment regimes. The aim of this study was to investigate the pharmacokinetics, endocrine effects and tolerability of chemically synthesized 8-PN in postmenopausal women.


METHODS
The study was performed using a randomized, double-blind, placebo-controlled, dose-escalation design with three groups of eight healthy postmenopausal women. In each group six subjects received 8-PN and two subjects placebo. 8-PN was given orally in doses of 50, 250 or 750 mg. Drug concentrations in serum, urine and faeces were measured up to 48 h and follicle-stimulating hormone/luteinizing hormone (LH) concentrations up to 24 h.


RESULTS
All treatments were well tolerated and associated with a low incidence of (drug unrelated) adverse events. Serum concentrations of free 8-PN showed rapid drug absorption and secondary peaks suggestive of marked enterohepatic recirculation. Independent of the treatment group, approximately 30% of the dose was recovered in excreta as free compound or conjugates over the 48-h observation period. The first C(max) and AUC(0-48 h) showed dose linearity with ratios of 1 : 4.5 : 13.6 (C(max)) and 1 : 5.2 : 17.1 (AUC). The750- mg dose decreased LH concentrations by 16.7% (95% confidence interval 0.5, 30.2).


CONCLUSIONS
Single oral doses of up to 750 mg 8-PN were well tolerated by postmenopausal women. The pharmacokinetic profile of 8-PN was characterized by rapid and probably complete enteral absorption, high metabolic stability, pronounced enterohepatic recirculation and tight dose linearity. The decrease in LH serum concentrations found after the highest dose demonstrates the ability of 8-PN to exert systemic endocrine effects in postmenopausal women.
Rad
M
M
Centre for Human Drug Research, Leiden, The Netherlands.
Hümpel
M
M
Schaefer
O
O
Schoemaker
R C
RC
Schleuning
W-D
WD
Cohen
A F
AF
Burggraaf
J
J
D000284:Administration, Oral; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D044950:Flavanones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006801:Humans; D007986:Luteinizing Hormone / Q000187:drug effects; D008875:Middle Aged; D048789:Phytoestrogens / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000187:drug effects
C119737:8-prenylnaringenin; D044950:Flavanones; D048789:Phytoestrogens; D011960:Receptors, Estrogen; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone