Koike M, Futaguchi S, Takahashi S, Sugeno K
Shionogi Research Laboratories, Shionogi and Co., Ltd., Osaka, Japan.
Drug Metab Dispos. 1988 Jul-Aug;16(4):609-15.
The new hypnotic, 5-[(2-aminoacetamido)methyl]-1-[p-chloro-2-(o- chlorobenzoyl)phenyl]-N,N-dimethyl-1H-1,2,4-triazole-3-carboxamide hydrochloride dihydrate (450191-S), is a ring-opened derivative of 1,4-benzodiazepine that is activated by spontaneous cyclization via a labile desglycylated metabolite (191DG). Pharmacokinetic comparison between 450191-S and its primary active metabolite, 8-chloro-6-(2-chlorophenyl)-N,N-dimethyl-4H-1,2,4-triazole[1,5-a][1,4] benzodiazepine-2-carboxamide (M-1), in rats revealed that higher levels of active metabolites were produced after 450191-S administration. To find the causes for this, in vivo and in vitro experiments were performed with the focus on hepatic uptake. Study of the absorption and distribution of radioactivity after intraduodenal administration of [14C]450191-S and [14C]M-1 revealed that most of the radioactivity was in the liver, with absorption of M-1 being rapid regardless of the dose and the absorption of 450191-S being slower at higher doses. Comparison of the portal and systemic metabolite levels showed the hepatic first-pass extraction after M-1 administration to be more effective than that after 450191-S administration. This was attributed to the labile intermediate, 191DG, which reduced the first-pass extraction in the liver. This reduction was confirmed by pharmacokinetic analysis after portal injection of 191DG in vivo and by incubation with liver slices in vitro. Thus, the presence of 191DG improved the bioavailability of active metabolites after 450191-S administration.
新型催眠药5-[(2-氨基乙酰氨基)甲基]-1-[对氯-2-(邻氯苯甲酰基)苯基]-N,N-二甲基-1H-1,2,4-三唑-3-甲酰胺盐酸盐二水合物(450191-S)是1,4-苯二氮䓬的开环衍生物,通过不稳定的去甘氨酰化代谢物(191DG)自发环化而被激活。450191-S与其主要活性代谢物8-氯-6-(2-氯苯基)-N,N-二甲基-4H-1,2,4-三唑并[1,5-a][1,4]苯二氮䓬-2-甲酰胺(M-1)在大鼠体内的药代动力学比较显示,给予450191-S后产生的活性代谢物水平更高。为找出原因,以肝脏摄取为重点进行了体内和体外实验。十二指肠内给予[14C]450191-S和[14C]M-1后放射性吸收和分布的研究表明,大部分放射性存在于肝脏中,M-1的吸收迅速,与剂量无关,而450191-S在高剂量时吸收较慢。门静脉和全身代谢物水平的比较显示,给予M-1后肝脏首过提取比给予450191-S后更有效。这归因于不稳定的中间体191DG,它降低了肝脏中的首过提取。体内门静脉注射191DG后的药代动力学分析以及体外与肝切片孵育证实了这种降低。因此,191DG的存在提高了给予450191-S后活性代谢物的生物利用度。