THE IN-VITRO DEGRADATION OF CISATRACURIUM, THE R,CIS-R'-ISOMER OF ATRACURIUM, IN HUMAN AND RAT PLASMA
THE IN-VITRO DEGRADATION OF CISATRACURIUM, THE R,CIS-R'-ISOMER OF ATRACURIUM, IN HUMAN AND RAT PLASMA
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DOI：
10.1016/0009-9236(95)90190-6
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发表时间：
1995-08-01
影响因子：
6.7
通讯作者：
DAHL, R
中科院分区：
文献类型：
--
作者：
WELCH, RM;BROWN, A;DAHL, R
目的：研究顺式阿曲库铵在水溶液缓冲液和人、大鼠血浆中的体外降解机理和降解速率。方法：将顺式阿曲库铵置于不同pH值的水缓冲液中孵育，或在人和大鼠血浆中用HEPES缓冲液维持pH 7.4。结果：在Sorenson的磷酸盐缓冲液中，顺式阿曲库铵通过通常被称为“霍夫曼消除”的化学过程自发降解。PH值越高，降解速度越快。从pH 6.4到7.8，顺式阿曲库铵的降解率增加了6.5倍，按摩尔计算，最终分解产物月桂糖苷占所有药物的比例。在pH为7.4时，顺式阿曲库铵的半衰期约为34.1±-2.1分钟。顺式阿曲库铵在人血浆中孵育后平均半衰期(+/-SD)为29.2+/-3.8分钟，符合Hofmann消除规律。除了月桂糖苷，与在索伦森的磷酸盐缓冲液中观察到的不同，形成了大量的单季铵盐醇，并慢慢降解为月桂糖苷。最终形成的微摩尔的劳达核苷占顺式阿曲库铵与人血浆孵育的总量。单季铵盐醇似乎是在霍夫曼消除的第一步中形成的单季铵盐丙烯酸酯的酯水解物。这一步酯酶参与顺式阿曲库铵降解的证据是基于对羧酸酯酶特异性抑制剂邻甲苯二氧磷酸盐(CBDP)的抑制研究。在人血浆中加入CBDP后，完全阻止了一季醇的形成，并将顺式阿曲库铵的降解转化为完全的霍夫曼消除。在大鼠血浆中，顺式阿曲库铵被羧酸酯酶降解，半衰期仅为3.5分钟。加入CBDP后，顺式阿曲库铵的半衰期延长至25min，与Hofmann消除一致。结论：顺式阿曲库铵在人血浆中降解的限速步骤是Hofmann消除，最初形成的是单季铵盐的丙烯酸酯。一季醇是由血浆酯酶(S)对丙烯酸单季铵盐进行酯水解而产生的，这一观察结果解释了顺式阿曲库铵临床研究中人体血浆中存在一季醇代谢物的原因。大鼠血浆相对于人血浆对顺式阿曲库铵的快速水解表明了血浆酯酶的主要物种差异(S)。
Objective: To assess the mechanism and rate of in vitro degradation of cisatracurium in aqueous buffer and in human and rat plasma.Methods: Cisatracurium was incubated in aqueous buffer at various pH values or in human and rat plasma maintained at pH 7.4 with HEPES buffer. Cisatracurium and the degradation products, laudanosine and the monoquaternary alcohol, were quantitated by HPLC with use of fluorescence detection.Results: In Sorenson's phosphate buffer, cisatracurium degraded spontaneously by a chemical process commonly referred to as ''Hofmann elimination.'' The rate of degradation increased with increasing pH. From pH 6.4 to 7.8 there was a 6.5-fold increase in the rate of degradation of cisatracurium and, on a molar basis, the final decomposition product laudanosine accounted for all of the drug. At a pH of 7.4, cisatracurium degraded with a half-life of about 34.1 +/- 2.1 minutes. Cisatracurium incubated in human plasma degraded with a mean (+/- SD) half-life of 29.2 +/- 3.8 minutes, which is consistent with Hofmann elimination. Besides laudanosine, and unlike that observed in Sorenson's phosphate buffer, significant amounts of the monoquaternary alcohol were formed that slowly degraded to laudanosine. The micromoles of laudanosine formed eventually accounted for the total amount of cisatracurium incubated with human plasma. The monoquaternary alcohol appears to be a product of ester hydrolysis of a monoquaternary acrylate formed during the first step in Hofmann elimination. Evidence for esterase involvement at this step in the degradation of cisatracurium was based on inhibition studies with O-cresyl benzodioxaphosphorin oxide (CBDP), a specific carboxylesterase inhibitor. The addition of CBDP to human plasma completely blocked the formation of monoquaternary alcohol and converted the degradation of cisatracurium to total Hofmann elimination. In rat plasma cisatracurium was hydrolyzed, with a half-life of only 3 1/2 minutes, by carboxylesterases. The addition of CBDP increased the half-life to 25 minutes, which is consistent with Hofmann elimination.Conclusion: In human plasma the rate-limiting step in the degradation of cisatracurium is Hofmann elimination, with the initial formation of a monoquaternary acrylate. The observation that the monoquaternary alcohol results from ester hydrolysis of the monoquaternary acrylate by plasma esterase(s) explains the presence of the monoquaternary alcohol metabolite in human plasma during clinical studies with cisatracurium. The rapid hydrolysis of cisatracurium by rat plasma relative to human indicates a major species difference in plasma esterase(s).