Chen Zhesheng, Agrawal Arun K, Franklin Ronald B, Leung Kwan H, Chiu Shuet-Hing Lee
Department of Basic Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065-0900, USA.
Pharm Res. 2004 Jun;21(6):996-9. doi: 10.1023/b:pham.0000029289.95033.b9.
To investigate the in vitro trans-esterification of 1-[2(R)-(2-amino-2-methylpropionylamino)-3-(1H-indol-3-yl)propionyl]-3(S)-benzyl-piperidine-3-carboxylic acid ethyl ester (compound A) and to determine the effects of ethanol on its in vivo pharmacokinetics in male Sprague-Dawley rats.
The effects of deuterated [d5]ethanol on the hydrolysis and trans-esterification of compound A in rat plasma and rat liver microsomes in the presence or absence of bis(p-nitrophenyl) phosphate (BNPP), a carboxylesterase inhibitor, were investigated. Following an oral pretreatment with deuterated ethanol in conjunction with an intravenous dose of compound A to rats, the pharmacokinetics of compound A and deuterated compound A were evaluated.
It was observed that the amount of deuterated compound A generated increased with increasing amounts of deuterated ethanol in incubates, whereas the amount of hydrolyzed product (compound B) decreased. BNPP inhibited both the hydrolysis and the trans-esterification of compound A. Furthermore, the pharmacokinetics of compound A in rats receiving ethanol was altered, such that the plasma clearance decreased by 1.5-fold and the elimination rate constant decreased by 2-fold. Deuterated compound A was determined, confirming that trans-esterification proceeded in vivo; approximately one third of the intravenous dose of compound A underwent trans-esterification.
In the presence of ethanol, compound A underwent trans-esterification catalyzed by carboxylesterases. Ethanol pretreatment resulted in a decrease in the in vivo clearance of compound A mainly due to trans-esterification with ethanol.
研究1-[2(R)-(2-氨基-2-甲基丙酰氨基)-3-(1H-吲哚-3-基)丙酰基]-3(S)-苄基哌啶-3-羧酸乙酯（化合物A）的体外酯交换反应，并确定乙醇对雄性Sprague-Dawley大鼠体内其药代动力学的影响。
研究了氘代[d5]乙醇在存在或不存在羧酸酯酶抑制剂双(对硝基苯基)磷酸酯(BNPP)的情况下对化合物A在大鼠血浆和大鼠肝微粒体中的水解和酯交换反应的影响。在给大鼠口服氘代乙醇预处理并静脉注射化合物A后，评估化合物A和氘代化合物A的药代动力学。
观察到孵育物中生成的氘代化合物A的量随氘代乙醇量的增加而增加，而水解产物（化合物B）的量减少。BNPP抑制了化合物A的水解和酯交换反应。此外，接受乙醇的大鼠体内化合物A的药代动力学发生了改变，血浆清除率降低了1.5倍，消除速率常数降低了2倍。测定了氘代化合物A，证实酯交换反应在体内发生；静脉注射剂量的化合物A中约有三分之一发生了酯交换反应。
在乙醇存在下，化合物A发生了由羧酸酯酶催化的酯交换反应。乙醇预处理导致化合物A的体内清除率降低，主要是由于与乙醇发生了酯交换反应。
