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Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs . dextrorphan using quinidine inhibition
Author(s) -
Moghadamnia A. A.,
RostamiHodjegan A.,
AbdulManap R.,
Wright C. E.,
Morice A. H.,
Tucker G. T.
Publication year - 2003
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2003.01853.x
Subject(s) - dextrorphan , dextromethorphan , quinidine , metabolite , pharmacology , chemistry , pharmacokinetics , active metabolite , potency , placebo , oral administration , medicine , in vitro , biochemistry , alternative medicine , pathology
Aims 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 h −1 , which overlapped with that extrapolated from in vitro data (12–261 l 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 µM. 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 (k e0 = 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.