title: Characterization of the time course of carbamazepine deinduction by an enzyme turnover model.
abstract: OBJECTIVE
  Carbamazepine is a potent inducer of drug metabolizing enzymes, which results in a number of clinically significant drug-drug interactions. Deinduction occurs when long-term carbamazepine therapy is discontinued. The goal of this study was to develop a population pharmacokinetic model to describe the time course of carbamazepine deinduction.
  
  
  METHODS
  Stable-labelled carbamazepine was administered intravenously on three occasions during the deinduction period to 15 patients with epilepsy for whom carbamazepine therapy was being discontinued. Data were analysed using a nonlinear mixed-effects model (NONMEM). An enzyme turnover model consisting of a one-compartment model linked with a hypothetical enzyme compartment was applied to characterize the time course of carbamazepine deinduction. Model evaluation was performed using the bootstrap approach and a visual predictive check.
  
  
  RESULTS
  In the final model, the deinduction process was accomplished by decreasing the rate of enzyme synthesis, resulting in a decrease in the relative amount of enzymes. The estimated rate constant for enzyme degradation was 0.00805 h-1, corresponding to a half-life of the combined enzymes of 86.1 hours (3.6 days).
  
  
  CONCLUSIONS
  An enzyme turnover model adequately characterized the experimental data. Based on the predicted enzyme half-life from the final model, the deinduction process should be completed within 2 weeks after carbamazepine therapy is terminated.
authors: Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota 55414, USA.
authors: Baralee
authors: B
authors: Punyawudho
authors: James C
authors: JC
authors: Cloyd
authors: Ilo E
authors: IE
authors: Leppik
authors: R Eugene
authors: RE
authors: Ramsay
authors: Susan E
authors: SE
authors: Marino
authors: Page B
authors: PB
authors: Pennell
authors: James R
authors: JR
authors: White
authors: Angela K
authors: AK
authors: Birnbaum
mesh_terms: D000328:Adult; D002220:Carbamazepine / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008954:Models, Biological; D013997:Time Factors
chemical_list: D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A