The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; Department of Experimental Medicine, Faculty of Medicine, University of British Columbia, Vancouver, B.C., Canada.
The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada.
Eur J Pharm Sci. 2019 Mar 15;130:173-180. doi: 10.1016/j.ejps.2019.01.016. Epub 2019 Jan 14.
The physiological and anti-cancer functions of vitamin D are accomplished primarily via 1α,25-dihydroxyvitamin D (calcitriol), whereas 20(S)-protopanaxadiol (aPPD) is a ginsenoside, which is isolated from Panax ginseng, with potential anti-cancer benefits. In the present study, we report a pharmacokinetic (PK) herb-nutrient interaction between calcitriol and aPPD in mice. A liquid chromatography mass spectrometry (LC/MS) method was developed using 4-phenyl-1,2,4-triazoline-3,5-dione derivatizing agent and we subsequently used the method to quantitate calcitriol in mouse serum. The limit of quantitation was 0.01 ng/ml which is approximately 100 fold lower than the previously reported assay from our laboratory. Calcitriol PK parameters were determined in non-tumor-bearing or C4-2 human prostate tumor-bearing nude mice following oral co-administration of calcitriol either alone or in combination with aPPD. Mice were pretreated with oral aPPD (70 mg/kg) or vehicle control twice daily for seven consecutive days, followed by a single oral dose of 4 μg/kg calcitriol alone or in combination with aPPD. Our PK results demonstrated that co-administration of calcitriol with aPPD (following pre-treatment with vehicle for seven days) resulted in a 35% increase in the area under the curve (AUC) and a 41% increase in the maximum serum concentration (Cmax) compared to the calcitriol only group. aPPD therefore significantly increased calcitriol serum exposure. We also saw a reduction in the time required to reach Cmax. In contrast, calcitriol PK in mice co-administered with calcitriol and aPPD as well as those pretreated seven consecutive days with aPPD was no different than that determined for the mice that received vehicle for seven days as pre-treatment. Co-administration of calcitriol with aPPD therefore could increase health benefits of vitamin D, however any increased risk of hypercalcemia, resulting from this combination approach, requires further investigation. Lastly, we surmise that a cytochrome P450 inhibition-based mechanism may contribute to the observed PK interaction.
维生素 D 的生理和抗癌功能主要通过 1α,25-二羟维生素 D（骨化三醇）来实现，而 20(S)-原人参二醇（aPPD）是一种从人参中分离出来的人参皂苷，具有潜在的抗癌益处。在本研究中，我们报告了维生素 D 代谢物骨化三醇与 aPPD 在小鼠体内的药代动力学（PK）草药-营养素相互作用。我们使用 4-苯基-1,2,4-三唑啉-3,5-二酮衍生剂开发了一种液相色谱-质谱（LC/MS）方法，并随后使用该方法定量检测小鼠血清中的骨化三醇。定量下限为 0.01ng/ml，大约是我们实验室之前报道的检测方法的 100 倍。在非肿瘤荷瘤或 C4-2 人前列腺肿瘤荷瘤裸鼠中，单独或联合使用 aPPD 口服给予骨化三醇后，确定骨化三醇 PK 参数。小鼠预先用 aPPD（70mg/kg）或载体对照每日两次连续处理 7 天，然后单独给予单次口服剂量 4μg/kg 骨化三醇或与 aPPD 联合给予。我们的 PK 结果表明，与单独给予骨化三醇相比，在预先用载体处理 7 天后联合给予 aPPD 可使 AUC 增加 35%，Cmax 增加 41%。aPPD 因此显著增加了骨化三醇的血清暴露。我们还观察到达到 Cmax 的时间减少。相比之下，与单独给予骨化三醇和 aPPD 的小鼠以及预先连续 7 天给予 aPPD 的小鼠相比，预先给予载体 7 天的小鼠的骨化三醇 PK 没有差异。因此，骨化三醇与 aPPD 的联合给药可能会增加维生素 D 的健康益处，但是这种联合治疗方法可能导致高钙血症风险增加，需要进一步研究。最后，我们推测细胞色素 P450 抑制为基础的机制可能导致观察到的 PK 相互作用。
