Single- and multiple-dose pharmacokinetics of genistein capsules in healthy chinese subjects: A phase I, randomized, open-label study

Background: Genistein capsules are currently being developed to treat osteoporosis in China. Genistein is extracted from the fruit of Sophora japonica Leguminosae. Objective: The objective of this study was to assess the pharmacokinetics of genistein capsules after single and multiple oral doses in healthy Chinese subjects. Methods: This was a Phase I, randomized, open-label, single- and multiple- dose study in healthy Chinese adults (aged 19–40 years). In the single-dose study, subjects were randomly assigned in a 1:1:1 ratio to receive genistein 50, 100, or 300 mg (in 50-mg capsules). To assess the effect of food on the pharmacokinetics, subjects in the 50-mg group were equally randomized again into fasting and postprandial (genistein was administered after a high-fat breakfast) groups according to a 2-way cross-over design. A separate equal-sized group of subjects were administered genistein 50 mg on day 1 (single dose), received no treatment on days 2 and 3, and were administered genistein 50 mg QD for 6 days (days 4–9) to obtain a multiple-dose pharmacokinetic profile. Because genistein is converted so rapidly and completely to glucuronidated genistein after administration, plasma concentrations of glucuronidated genistein were determined using a validated high-performance liquid chromatography/ tandem mass spectrometry method. Drug tolerability was assessed by monitoring adverse events (AEs) and laboratory parameters. Results: The study enrolled 40 healthy subjects (24 men, 16 women; 10 each in the 50-, 100-, and 300-mg single-dose groups and 10 in the multiple-dose group). Three subjects voluntarily withdrew (2 in the 100-mg group and 1 in the 300-mg group) before study drug administration. Thirty-seven subjects (24 men, 13 women) completed the study and were included in the analysis. The mean (SD) values of the single-dose genistein 50-, 100-, and 300-mg groups were as follows: Tmax, 6.0 (2.4), 7.4 (2.4), and 5.6 (1.2) hours, respectively; tl/2, 13.0 (4.0), 12.6 (5.8), and 9.4 (1.1) hours; AUC0−t, 3344 (1635), 8389 (5164), and 9361 (2428) ng/mL · h−1; and Cmax , 218.7 (68.6), 435.7 (202.1), and 553.4 (152.8) ng/mL. The plasma glucuronidated genistein concentrations were directly proportional to the administered dose over the range of 50 to 100 mg and increased nonproportionately with the 300-mg dose. No statistically significant differences in pharmacokinetic parameters were found in the fasting group compared with the postprandial group. In the multiple-dose group, the mean (SD) steady-state pharmacokinetic parameters on day 9 were similar to those following a single dose of genistein on day 1 (Tmax, 6.0 [1.0] vs 5.9 [1.5] hours, respectively; tl/2, 9.5 [1.5] vs 9.1 [1.5] hours; AUC0−t, 2830 [1541] vs 2078 [1308] ng/mL · h−1; Cmax, 203.1 [130.9] vs 168.4 [105.7] ng/mL). All AEs were assessed as mild or moderate and resolved without treatment, with the exception of elevated alanine aminotransferase and aspartate aminotransferase activities in one subject that resolved with treatment. Conclusions: The pharmacokinetics of glucuronidated genistein appeared to fit the linear-dose range of genistein 50 to 100 mg, but not the 300-mg dose in these healthy Chinese volunteers. Food consumption did not significantly affect the pharmacokinetic properties. No significant differences were observed in the pharmacokinetic parameters after multiple doses of genistein compared with a single dose, suggesting that the drug did not accumulate after multiple doses.