Raish Mohammad, Ahmad Ajaz, Ansari Mushtaq Ahmad, Alkharfy Khalid M, Ahad Abdul, Al-Jenoobi Fahad I, Al-Mohizea Abdullah M, Khan Altaf, Ali Naushad
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Epilepsy Res. 2019 Jul;153:14-18. doi: 10.1016/j.eplepsyres.2019.03.012. Epub 2019 Mar 22.
Dietary supplements, herbal medicines, and other foods may affect the pharmacokinetics and/or pharmacodynamics of carbamazepine (CBZ), which may possibly lead to potential drug-drug/herb-drug interactions, as CBZ has a narrow therapeutic window. Sinapic acid (SA) is a bioactive phytoconstituent used as a dietary supplement for the treatment of epilepsy. This study determined the effects of SA on the pharmacokinetics of CBZ and proposed a possible interaction mechanism in twenty-four male wistar rats (180-210 g). A single CBZ dose (80 mg/kg) was administered orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The CBZ concentration in plasma samples was determined by using a sensitive reversed-phase high-performance liquid chromatography assay. The pharmacokinetic parameters were calculated by using non-compartmental analysis. Significance was determined through Dunnett's multiple comparison test or one-way analysis of variance as appropriate; p < 0.05 were considered significant. The change in the pharmacokinetic parameters (C, T, AUC, AUC, T, and k) of CBZ was evaluated after the administration of CBZ alone or after CBZ co-administration with SA pretreatment. The plasma concentration of CBZ was higher after SA pretreatment than that without pretreatment. The pharmacokinetics of orally administered CBZ were found to be significantly altered (p < 0.05) in rats pretreated with SA compared to those in rats administered CBZ alone. The increases in the C, AUC, T, and MRT of CBZ were 29.79%, 57.18%, 77.18%, and 58.31%, respectively, whereas the k and apparent oral CL/F were significantly reduced (p < 0.05) in rats pretreated with SA compared to those in rats not pretreated with SA (43.87% and 42.50%, respectively). However, no significant change was observed in the T of CBZ in rats pretreated with SA compared to that in rats that did not receive pretreatment. The enhancement in Cmax, AUC, T and MRT and the reduction in K and CL/F values resulted from the significant inhibition of CYP3 A2, the CYP2C11-mediated metabolism of CBZ in the liver, and the inhibition of intestinal P-glycoprotein/MDR1, which enhanced the rate of CBZ absorption. Further studies are required to determine the clinical relevance of these observations.
膳食补充剂、草药和其他食物可能会影响卡马西平（CBZ）的药代动力学和/或药效学，由于CBZ的治疗窗较窄，这可能会导致潜在的药物-药物/草药-药物相互作用。芥子酸（SA）是一种生物活性植物成分，用作治疗癫痫的膳食补充剂。本研究在24只雄性Wistar大鼠（180 - 210克）中确定了SA对CBZ药代动力学的影响，并提出了一种可能的相互作用机制。对有或没有SA预处理（每天口服20毫克/千克，共7天，n = 6）的大鼠口服单次CBZ剂量（80毫克/千克）。使用灵敏的反相高效液相色谱法测定血浆样品中的CBZ浓度。通过非房室分析计算药代动力学参数。根据情况通过Dunnett多重比较检验或单因素方差分析确定显著性；p < 0.05被认为具有显著性。在单独给予CBZ或CBZ与SA预处理联合给药后，评估CBZ药代动力学参数（Cmax、Tmax、AUC0-t、AUC0-∞、T1/2和k）的变化。SA预处理后CBZ的血浆浓度高于未预处理时。与单独给予CBZ的大鼠相比，SA预处理的大鼠口服CBZ的药代动力学有显著改变（p < 0.05）。SA预处理的大鼠中CBZ的Cmax、AUC0-∞、Tmax和MRT的增加分别为29.79%、57.18%、77.18%和58.31%，而与未用SA预处理的大鼠相比，SA预处理的大鼠中k和表观口服CL/F显著降低（分别为43.87%和42.50%）。然而，与未接受预处理的大鼠相比，SA预处理的大鼠中CBZ的T1/2没有观察到显著变化。Cmax、AUC0-∞、Tmax和MRT的增加以及K和CL/F值的降低是由于CYP3A2、肝脏中CBZ的CYP2C11介导的代谢受到显著抑制，以及肠道P-糖蛋白/MDR1受到抑制，从而提高了CBZ的吸收速率。需要进一步研究来确定这些观察结果的临床相关性。
