Lin J H, Sugiyama Y, Hanano M, Awazu S
Drug Metab Dispos. 1984 Mar-Apr;12(2):253-6.
In our previous study [Lin, Sugiyama, Awazu, and Hanano: J. Pharmacokin. Biopharm. 10,649 (1982)], we successfully applied a physiological pharmacokinetic model to quantitative prediction of the elimination and distribution kinetics of ethoxybenzamide in rats and rabbits. The predictions of the time course of ethoxybenzamide concentrations in plasma were good at lower doses (10 and 20 mg/kg), whereas those at high dose (80 mg/kg) were poor. In the present study, therefore, product inhibition was suspected and examined. Product inhibition of ethoxybenzamide deethylation by its metabolite, salicylamide, was demonstrated both in vivo and in vitro studies. The plasma disappearances of ethoxybenzamide after a 20 mg/kg iv injection were determined both in the control and the salicylamide-treated rabbits. In the salicylamide-treated rabbits, the plasma disappearance of ethoxybenzamide was significantly delayed compared to that in control rabbits. This delay was quantitatively explained by the physiological pharmacokinetic model taking the competitive-type of product inhibition into consideration. The apparent dissociation constant for the salicylamide-enzyme complex in vivo was estimated as 0.14 mM. The inhibition of ethoxybenzamide de-ethylation by salicylamide was observed also in in vitro study using liver microsome of rabbits.
在我们之前的研究中[林、杉山、粟津和花野：《药代动力学与生物药剂学杂志》10,649 (1982)]，我们成功地应用生理药代动力学模型对大鼠和兔子体内乙氧苯甲酰胺的消除和分布动力学进行了定量预测。在较低剂量（10和20毫克/千克）时，血浆中乙氧苯甲酰胺浓度随时间变化的预测结果良好，而在高剂量（80毫克/千克）时预测结果较差。因此，在本研究中，我们怀疑并研究了产物抑制作用。在体内和体外研究中均证实了乙氧苯甲酰胺的代谢产物水杨酰胺对其脱乙基作用具有产物抑制作用。在对照兔和经水杨酰胺处理的兔中，静脉注射20毫克/千克乙氧苯甲酰胺后测定其血浆消除情况。与对照兔相比，经水杨酰胺处理的兔中乙氧苯甲酰胺的血浆消除明显延迟。考虑到竞争性产物抑制作用，该生理药代动力学模型对这种延迟进行了定量解释。体内水杨酰胺 - 酶复合物的表观解离常数估计为0.14毫摩尔。在使用兔肝微粒体的体外研究中也观察到了水杨酰胺对乙氧苯甲酰胺脱乙基作用的抑制。
