Abramson F P, Lutz M P
Drug Metab Dispos. 1986 Jan-Feb;14(1):46-51.
Rifampin is known to be an important stimulus to drug-metabolizing enzymes and can also induce the production of alpha 1-acid glycoprotein (AGP). We have studied the time course for induction of drug metabolizing capability as assessed by the clearance of antipyrine and the plasma concentration of AGP following a chronic course of rifampin in dogs. The kinetics of the induction process were observed during a 22-day treatment period, and the wash-out period kinetics were followed for another 3 weeks. Rifampin kinetics were measured at the end of the 22-day dosing period. Both antipyrine clearance and AGP concentration were significantly increased by the rifampin treatment; antipyrine clearance doubled and AGP concentrations nearly tripled. When analyzed by a newly developed kinetic model of induction, it was determined that the time course for AGP or antipyrine clearance was not governed by a single rate constant. The second rate constant did not represent the accumulation or persistence of rifampin (t1/2 = 4.4 hr). It is hypothesized that one or more synthesis precursors to the enzymes which produce AGP or clear antipyrine are also rate limiting. This is the first example in which an induction/deinduction experiment has been interpreted from beginning to end with a three-step kinetic model. It demonstrates the applicability of this model and recommends its use in other induction experiments.
已知利福平是药物代谢酶的重要刺激物，还可诱导α1-酸性糖蛋白（AGP）的产生。我们研究了在犬类中给予利福平慢性疗程后，通过安替比林清除率和AGP血浆浓度评估的药物代谢能力诱导的时间进程。在22天的治疗期内观察诱导过程的动力学，并在另外3周内跟踪清除期动力学。在22天给药期结束时测量利福平动力学。利福平治疗使安替比林清除率和AGP浓度均显著增加；安替比林清除率翻倍，AGP浓度几乎增至三倍。当通过新开发的诱导动力学模型进行分析时，确定AGP或安替比林清除率的时间进程不受单一速率常数的控制。第二个速率常数并不代表利福平的蓄积或持续存在（t1/2 = 4.4小时）。据推测，产生AGP或清除安替比林的酶的一种或多种合成前体也是限速因素。这是首次使用三步动力学模型从头到尾解释诱导/去诱导实验的例子。它证明了该模型的适用性，并建议在其他诱导实验中使用。
