Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: Dextromethorphan vs. dextrorphan using quinidine inhibition

A. A. Moghadamnia, A. Rostami-Hodjegan, Roslina Abd. Manap, C. E. Wright, A. H. Morice, G. T. Tucker

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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 hydrobromide 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 1 h-1, which overlapped with that extrapolated from in vitro data (12-261 1 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 (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.

Original languageEnglish
Pages (from-to)57-67
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume56
Issue number1
DOIs
Publication statusPublished - 1 Jul 2003
Externally publishedYes

Fingerprint

Dextrorphan
Dextromethorphan
Quinidine
Antitussive Agents
Pharmaceutical Preparations
Bromides
Cough
Citric Acid
Cross-Over Studies

Keywords

  • Active metabolite
  • CYP2D6
  • Population pharmacokinetics-pharmacodynamics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite : Dextromethorphan vs. dextrorphan using quinidine inhibition. / Moghadamnia, A. A.; Rostami-Hodjegan, A.; Abd. Manap, Roslina; Wright, C. E.; Morice, A. H.; Tucker, G. T.

In: British Journal of Clinical Pharmacology, Vol. 56, No. 1, 01.07.2003, p. 57-67.

Research output: Contribution to journalArticle

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abstract = "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 hydrobromide 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 1 h-1, which overlapped with that extrapolated from in vitro data (12-261 1 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 (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.",
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AU - Moghadamnia, A. A.

AU - Rostami-Hodjegan, A.

AU - Abd. Manap, Roslina

AU - Wright, C. E.

AU - Morice, A. H.

AU - Tucker, G. T.

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AB - 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 hydrobromide 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 1 h-1, which overlapped with that extrapolated from in vitro data (12-261 1 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 (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.

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