Gender-related differences in pharmacokinetics, tissue distribution, and excretion of 20(R)-25-methoxyl-dammarane-3β,12β,20-triol and its metabolite in rats and anti-ovarian cancer evaluation

Our previous study suggests a well-defined pharmacological activity of 20(R)-25-methoxyl-dammarane-3 beta,12 beta,20-triol (AD-1) and its metabolite 20(R)-dammarane-3 beta,12 beta,20,25-tetrol (AD-2). The current study aims to investigate the gender-related differences in pharmacokinetics, tissue distribution, and excretion of AD-1 and its metabolite in both male and female rats. A sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometric (UPLC-MS/MS) method was developed for the simultaneous determination of AD-1 and AD-2 levels in plasma, various tissues, bile, urine, and feces. The results showed that AD-1 and its metabolite were rapidly distributed and eliminated from rat plasma; linear dynamics (r >= 0.8042) was observed in the dose range of 10-40mg/kg. Compared with male rats, AD-1 and AD-2 were eliminated slowly from the plasma of female rats, and significant gender-related differences were observed in the pharmacokinetics as well as tissue distribution, however, long-term accumulation was not observed. Gender also significantly influenced excretion via urine and feces, but this effect was not observed in the bile excretion study. In rats, AD-1 and its metabolite were highly distributed in female genital organs, which implied that AD-1 and AD-2 might have a great potential for the treatment of ovarian cancer. Therefore, this study first investigated the in vitro activity of AD-1 and AD-2 for ovarian cancer. The results indicated that AD-1, AD-2, and Mitomycin C (Mito C) obviously inhibited the growths of ovarian cancer cells (HO-8910 and OVCAR(R)-3). At 40, 80 mu M, AD-1, AD-2 reduced growth of two ovarian Cancer cells by 80%, were more effective than Mito C, and AD-1 showed stronger anti-ovarian cancer cell activity than AD-2. The results provide a theoretical basis for the future studies of AD-1 and AD-2 in ovarian cancer. (C) 2018 Elsevier B.V. All rights reserved.