title: Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs. dextrorphan using quinidine inhibition.
abstract: OBJECTIVE
  To define the relative antitussive effect of dextromethorphan (DEX) and its primary metabolite dextrorphan (DOR) after administration of DEX.
  
  
  METHODS
  Data were analysed from a double-blind, randomized cross-over study in which 22 subjects received the following oral treatments: (i) placebo; (ii) 30 mg DEX hydro-bromide; (iii) 60 mg DEX hydro-bromide; and (iv) 30 mg DEX hydro-bromide preceded at 1 h by quinidine HCl (50 mg). Cough was elicited using citric acid challenge. Pharmacokinetic data from all non-placebo arms of the study were fitted simultaneously. The parameters were then used as covariates in a link PK-PD model of cough suppression using data from all treatment arms.
  
  
  RESULTS
  The best-fit PK model assumed two- and one-compartment PK models for DEX and DOR, respectively, and competitive inhibition of DEX metabolism by quinidine. The intrinsic clearance of DEX estimated from the model ranged from 59 to 1536 l x h(-1), which overlapped with that extrapolated from in vitro data (12-261 l x h(-1)) and showed similar variation (26- vs. 21-fold, respectively). The inhibitory effect of quinidine ([I]/Ki) was 19 (95% confidence interval of mean: 18-20) with an estimated average Ki of 0.017 microM. Although DEX and DOR were both active, the potency of the antitussive effect of DOR was 38% that of DEX. A sustained antitussive effect was related to slow removal of DEX/DOR from the effect site (ke0 = 0.07 h(-1)).
  
  
  CONCLUSIONS
  Physiologically based PK modelling with perturbation of metabolism using an inhibitor allowed evaluation of the antitussive potency of DOR without the need for separate administration of DOR.
authors.affiliation: Molecular Pharmacology & Pharmacogenetics, Division of Clinical Sciences (South), University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Moghadamnia
authors.forename: A
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: R
authors.initials: R
authors.lastname: Abdul-Manap
authors.forename: C E
authors.initials: CE
authors.lastname: Wright
authors.forename: A H
authors.initials: AH
authors.lastname: Morice
authors.forename: G T
authors.initials: GT
authors.lastname: Tucker
mesh_terms: D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D000996:Antitussive Agents; D003371:Cough / Q000503:physiopathology / Q000517:prevention & control; D018592:Cross-Over Studies; D003915:Dextromethorphan / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D003917:Dextrorphan / Q000378:metabolism* / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D011802:Quinidine / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D000996:Antitussive Agents; D003917:Dextrorphan; D003915:Dextromethorphan; D011802:Quinidine