Tsuji A, Miyamoto E, Kagami I, Sakaguchi H, Yamana T
J Pharm Sci. 1978 Dec;67(12):1701-4. doi: 10.1002/jps.2600671218.
An equation was derived for the simultaneous assessment of rate constatns for absorption and nonenzymatic degradation of unstable drugs in in situ absorption experiments. The equation was substantiated by using a variety of beta-lactam antibiotics in the recirculation technique through the rat small intestine. Plots of the apparent first-order rate constant for the disappearance of the drug from the gut lumen versus the reciprocal of the volume of recirculating solution yielded a straight line with a slope equal to the intrinsic absorption rate constant and with an intercept equal to the nonenzymatic degradation rate constant in the GI lumen. The kinetic method for evaluation of the absorption rate constant also was developed for a more complex situation in the GI lumen involving absorption, nonenzymatic degradation, and enzymatic metabolism. The proposed method was confirmed with carbenicillin indanyl, which was metabolized rapidly to carbenicillin by the action of nonspecific esterase in the intestine. In the absence of information of Michaelis--Menten kinetic parameters, the present method is advantageous for evaluation of the intrinsic absorption rate of all unstable drugs.
推导了一个用于在原位吸收实验中同时评估不稳定药物吸收速率常数和非酶降解速率常数的方程。通过在大鼠小肠的再循环技术中使用多种β-内酰胺抗生素，证实了该方程。药物从肠腔中消失的表观一级速率常数与再循环溶液体积的倒数作图，得到一条直线，其斜率等于内在吸收速率常数，截距等于胃肠道腔中的非酶降解速率常数。还针对胃肠道腔中涉及吸收、非酶降解和酶代谢的更复杂情况，开发了评估吸收速率常数的动力学方法。所提出的方法用羧苄青霉素茚满酯得到了证实，羧苄青霉素茚满酯在肠道中非特异性酯酶的作用下迅速代谢为羧苄青霉素。在缺乏米氏动力学参数信息的情况下，本方法有利于评估所有不稳定药物的内在吸收速率。
