Pharmacokinetics and organ distribution of diarylheptanoid phytoestrogens from Curcuma comosa in rats

Abstract

Curcuma comosa is widely used as a traditional herbal medicine for gynecological diseases in South East Asia. Previous studies reported that it has phytoestrogenic activity, and several diarylheptanoids were found to be the active constituents. In this study, the pharmacokinetics profile and organ distribution of three active compounds of C. comosa hexane extract were investigated. Rats were separately administered C. comosa hexane extract intravenously at the dose of 125 mg/kg and orally at the doses of 125 and 250 mg/kg body weight, after which blood and target organs were collected at specified time intervals from 0 to 24 h. HPLC was used to measure the concentration of three major compounds, (6E)-1,7-diphenylhept-6-en-3-one (DPH1), (4E,6E)-1,7-diphenylhepta-4,6-dien-3-ol (DPH2), and (6E)-1,7-diphenylhept-6-en-3-ol (DPH3), which were found to be present in the blood and tissues and were subsequently used as markers. In the intravenous study, the volumes of distribution (V(d)) were 1.06, 8.57, and 6.56 L/kg and clearance values (CL(s)) were 0.28, 5.56, and 3.39 L/kg/h for DPH1, DPH2, and DPH3, respectively. After oral administration, the three major compounds of both doses reached a maximum systemic concentration at 2 h with maximum concentration (C(max)) of 0.85, 0.17, and 0.53 mg/L for the lower dose and 1.46, 0.17, and 0.61 mg/L for the higher dose. The bioavailabilities were 31.2, 24.01, and 31.56% for lower dose and 22.61, 17.66, and 17.73% for higher dose with a terminal half-life (t(1/2)) of 10.86, 6.3, and 4.62 h for lower dose and 3.85, 2.77, and 2.10 h for higher dose for DPH1, DPH2, and DPH3, respectively. These three major compounds are all found distributed in the brain, liver, kidneys, ovaries, and uterus after oral and intravenous administration and their related pharmacokinetic parameters are described. This study provides the essential pharmacokinetic data for diarylheptanoid phytoestrogenic compounds of C. comosa extract which are required for clinical dose and dosage design.

Determination of the Marker Diarylheptanoid Phytoestrogens in <i>Curcuma comosa</i> Rhizomes and Selected Herbal Medicinal Products by HPLC-DAD

“…4,5,24) Moreover, no reports about the HPLC analysis of 1 existed in previous literature. Thus, separation of both non-polar and semi-polar diarylheptanoids was carried out using a reverse phase chromatography with stepwise elution instead of those of normal phase column in isocratic mode.…”

“…Thus, separation of both non-polar and semi-polar diarylheptanoids was carried out using a reverse phase chromatography with stepwise elution instead of those of normal phase column in isocratic mode. 4,24) The effects of various factors were then carefully analyzed to select the optimal chromatographic conditions. Acidification of the mobile phase with acetic acid resulted in a symmetry of the peaks and a column temperature was maintained at 35°C to provide the reproducible peaks.…”

“…It has traditionally been used for the treatment of uterine inflammation, postpartum uterine bleeding, premenopausal bleeding, stomachic problems, and tonic being the main uses. 4,5) Currently, many traditional Thai medicines and dietary supplemental products containing C. comosa are gained popularity in the market for the treatment of gynecological disorders and health promotion in peri-and postmenopausal women.…”

“…The diarylheptanoids 1-3 are not commercially available and they must be isolated from the plant material. Su et al 4) selected three diarylheptanoids including (6E)-1,7-diphenylhept-6-en-3-one (does not appear in the submitted study), (4E,6E)-1,7-diphenylhepta-4,6-dien-3-ol ("2" of the submitted study), and (6E)-1,7-diphenylhept-6-en-3-ol ("3" of the submitted study) as the compounds to be the markers in quality control of C. comosa. In the submitted study, compound 1 was selected instead of (6E)-1,7-diphenylhept-6-en-3-one because 1-3 are most likely the major diarylheptanoids in the plant rhizome responsible for many pharmacological effects both in vitro and in vivo.…”

“…Only two isocratic HPLC methods using the combination of n-hexane and dichloromethane as eluent and a normal phase column as stationary phase have been described for the simultaneous analysis of 2 and 3 in the hexane extract of C. comosa. 4,24) Studies of the HPLC analysis of 1 have not been reported up to now. These methods are limited due to the interfering effects of some chemical constituents that coeluted when analysis of the samples extracted with other more polar solvents compared to hexane.…”