RT Journal Article
SR Electronic
T1 The kinetics of induction by rifampin of alpha 1-acid glycoprotein and antipyrine clearance in the dog.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 46
OP 51
VO 14
IS 1
A1 Abramson, F P
A1 Lutz, M P
YR 1986
UL http://dmd.aspetjournals.org/content/14/1/46.abstract
AB 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.