Abstract

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.