Sugiyama Ikuo, Murayama Norie, Kuroki Ayaka, Kota Jagannath, Iwano Shunsuke, Yamazaki Hiroshi, Hirota Takashi
a Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences , Tokyo University of Science , Chiba , Japan .
b Drug Metabolism and Pharmacokinetics, Novartis Pharma K.K. , Tokyo , Japan .
Xenobiotica. 2016 Sep;46(9):765-74. doi: 10.3109/00498254.2015.1118774. Epub 2015 Dec 29.
Anti-epileptic drug oxcarbazepine is structurally related to carbamazepine, but has reportedly different metabolic pathway. Auto-induction potentials of oxcarbazepine, its pharmacologically active metabolite 10-hydroxyoxcarbazepine and carbamazepine were evaluated by cytochrome P450 (CYP) 1A2, CYP2B6 and CYP3A4 mRNA levels and primary metabolic rates using human hepatocytes and HepaRG cells. For the CYP1A2 the induction potential determined as the fold change in mRNA levels was 7.2 (range: 2.3-11.5) and 10.0 (6.2-13.7) for oxcarbazepine and carbamazepine, respectively, while 10-hydroxyoxcarbazepine did not induce. The fold change in mRNA levels for CYP2B6 was 11.5 (3.2-19.3), 7.0 (2.5-10.8) and 14.8 (3.1-29.1) for oxcarbazepine, 10-hydroxyoxcarbazepine and carbamazepine, respectively. The fold change for CYP3A4 induction level by oxcarbazepine, 10-hydroxyoxcarbazepine and carbamazepine was 3.5 (1.2-7.4), 2.7 (0.8-5.7) and 8.3 (3.5-14.5), respectively. The data suggest lower induction potential of oxcarbazepine and 10-hydroxyoxcarbazepine relative to carbamazepine. The results in HepaRG cells showed similar trend as the human hepatocytes. After incubation for 72 h in hepatocytes and HepaRG cells, auto-induction was evident for only carbamazepine metabolism. The 10-keto group instead of double bond at C10 position is evidently a determinant factor for limited auto-induction of P450 enzymes by oxcarbazepine.
抗癫痫药物奥卡西平在结构上与卡马西平相关，但据报道其代谢途径不同。利用人肝细胞和HepaRG细胞，通过细胞色素P450（CYP）1A2、CYP2B6和CYP3A4 mRNA水平及初级代谢率，评估了奥卡西平、其药理活性代谢物10 - 羟基奥卡西平和卡马西平的自身诱导潜力。对于CYP1A2，以mRNA水平的倍数变化确定的诱导潜力，奥卡西平和卡马西平分别为7.2（范围：2.3 - 11.5）和10.0（6.2 - 13.7），而10 - 羟基奥卡西平无诱导作用。CYP2B6的mRNA水平倍数变化，奥卡西平、10 - 羟基奥卡西平和卡马西平分别为11.5（3.2 - 19.3）、7.0（2.5 - 10.8）和14.8（3.1 - 29.1）。奥卡西平、10 - 羟基奥卡西平和卡马西平对CYP3A4诱导水平的倍数变化分别为3.5（1.2 - 7.4）、2.7（0.8 - 5.7）和8.3（3.5 - 14.5）。数据表明，相对于卡马西平，奥卡西平和10 - 羟基奥卡西平的诱导潜力较低。HepaRG细胞中的结果与人类肝细胞显示出相似趋势。在肝细胞和HepaRG细胞中孵育72小时后，仅卡马西平代谢出现明显的自身诱导。奥卡西平对P450酶有限的自身诱导作用，C10位的10 - 酮基而非双键显然是一个决定因素。
