Xyloketal B, a marine compound, acts on a network of molecular proteins and regulates the activity and expression of rat cytochrome P450 3a: a bioinformatic and animal study

Su, Junhui; Chang, Cui; Xiang, Qi; Zhou, Zhi-Wei; Luo, Rong; Yang, Lun; He, Zhi-Xu; Yang, Hongtu; Li, Jianan; Bei, Yu; Xu, Jinmei; Zhang, Minjing; Zhang, Qihao; Su, Zhijian; Huang, Yadong; Pang, Jiyan; Zhou, Shu-Feng

In addition, compared with normal saline or soybean oil, a single dose of ketoconazole 75 mg/kg significantly increased the C max , AUC 0-t , and AUC 0-inf of midazolam by 3.5-fold, 3.6-fold, and 3.6-fold, respectively, and decreased the V/F and CL/F of midazolam by 75.2% and 73.7%, respectively. Further, compared with vehicle-treated rats, the ratio of the plasma AUC of 1′-OH-MDZ over that of midazolam was significantly decreased by 66.2% in rats treated orally with ketoconazole 75 mg/kg. Collectively, the above results show that XKB 7 or 14 mg/kg significantly reduced the metabolism of midazolam in rats without marked dose dependence, probably due to the decreased activity of Cyp3a. Since the total clearance and distribution of midazolam and its metabolite were not altered by XKB, the possibility of modulation of other pathways by XKB cannot be excluded.