The antitussive effect of dextromethorphan in relation to CYP2D6 activity

Roslina Abd. Manap, C. E. Wright, A. Gregory, A. Rostami-Hodjegan, S. T. Meller, G. R. Kelm, M. S. Lennard, G. T. Tucker, A. H. Morice

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Aims. To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. Methods. Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. Results. Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P < 0.001). The mean (± s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P < 0.001; 95% CI of difference +80, +327) and QDEX30/placebo (P < 0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX3O (P = 0.071, -7, +241; P = 0.254, -37, +211; P = 0.187, -29, +219, respectively). Conclusions. A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.

Original languageEnglish
Pages (from-to)382-387
Number of pages6
JournalBritish Journal of Clinical Pharmacology
Volume48
Issue number3
DOIs
Publication statusPublished - 1999
Externally publishedYes

Fingerprint

Antitussive Agents
Dextromethorphan
Cytochrome P-450 CYP2D6
Placebos
Cough
Quinidine
Dextrorphan
Citric Acid
Cross-Over Studies
Inhalation
Area Under Curve
Phenotype

Keywords

  • Antitussive effect
  • CYP2D6
  • Dextromethorphan
  • Genetic polymorphism

ASJC Scopus subject areas

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

Cite this

Abd. Manap, R., Wright, C. E., Gregory, A., Rostami-Hodjegan, A., Meller, S. T., Kelm, G. R., ... Morice, A. H. (1999). The antitussive effect of dextromethorphan in relation to CYP2D6 activity. British Journal of Clinical Pharmacology, 48(3), 382-387. https://doi.org/10.1046/j.1365-2125.1999.00029.x

The antitussive effect of dextromethorphan in relation to CYP2D6 activity. / Abd. Manap, Roslina; Wright, C. E.; Gregory, A.; Rostami-Hodjegan, A.; Meller, S. T.; Kelm, G. R.; Lennard, M. S.; Tucker, G. T.; Morice, A. H.

In: British Journal of Clinical Pharmacology, Vol. 48, No. 3, 1999, p. 382-387.

Research output: Contribution to journalArticle

Abd. Manap, R, Wright, CE, Gregory, A, Rostami-Hodjegan, A, Meller, ST, Kelm, GR, Lennard, MS, Tucker, GT & Morice, AH 1999, 'The antitussive effect of dextromethorphan in relation to CYP2D6 activity', British Journal of Clinical Pharmacology, vol. 48, no. 3, pp. 382-387. https://doi.org/10.1046/j.1365-2125.1999.00029.x
Abd. Manap, Roslina ; Wright, C. E. ; Gregory, A. ; Rostami-Hodjegan, A. ; Meller, S. T. ; Kelm, G. R. ; Lennard, M. S. ; Tucker, G. T. ; Morice, A. H. / The antitussive effect of dextromethorphan in relation to CYP2D6 activity. In: British Journal of Clinical Pharmacology. 1999 ; Vol. 48, No. 3. pp. 382-387.
@article{4f2d164758134ad794b6c16e9e1b2e8e,
title = "The antitussive effect of dextromethorphan in relation to CYP2D6 activity",
abstract = "Aims. To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. Methods. Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10{\%} citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. Results. Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P < 0.001). The mean (± s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8{\%} (11), 17{\%} (14.5), 25{\%} (16.2) and 25{\%} (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P < 0.001; 95{\%} CI of difference +80, +327) and QDEX30/placebo (P < 0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX3O (P = 0.071, -7, +241; P = 0.254, -37, +211; P = 0.187, -29, +219, respectively). Conclusions. A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10{\%} difference in cough response, the observed differences for other contrasts were less than 10{\%}, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.",
keywords = "Antitussive effect, CYP2D6, Dextromethorphan, Genetic polymorphism",
author = "{Abd. Manap}, Roslina and Wright, {C. E.} and A. Gregory and A. Rostami-Hodjegan and Meller, {S. T.} and Kelm, {G. R.} and Lennard, {M. S.} and Tucker, {G. T.} and Morice, {A. H.}",
year = "1999",
doi = "10.1046/j.1365-2125.1999.00029.x",
language = "English",
volume = "48",
pages = "382--387",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - The antitussive effect of dextromethorphan in relation to CYP2D6 activity

AU - Abd. Manap, Roslina

AU - Wright, C. E.

AU - Gregory, A.

AU - Rostami-Hodjegan, A.

AU - Meller, S. T.

AU - Kelm, G. R.

AU - Lennard, M. S.

AU - Tucker, G. T.

AU - Morice, A. H.

PY - 1999

Y1 - 1999

N2 - Aims. To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. Methods. Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. Results. Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P < 0.001). The mean (± s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P < 0.001; 95% CI of difference +80, +327) and QDEX30/placebo (P < 0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX3O (P = 0.071, -7, +241; P = 0.254, -37, +211; P = 0.187, -29, +219, respectively). Conclusions. A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.

AB - Aims. To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. Methods. Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of: (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. Results. Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX:DOR) plasma AUC(96) (0.04 vs 1.81, P < 0.001). The mean (± s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo (P < 0.001; 95% CI of difference +80, +327) and QDEX30/placebo (P < 0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX3O (P = 0.071, -7, +241; P = 0.254, -37, +211; P = 0.187, -29, +219, respectively). Conclusions. A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.

KW - Antitussive effect

KW - CYP2D6

KW - Dextromethorphan

KW - Genetic polymorphism

UR - http://www.scopus.com/inward/record.url?scp=0032842655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032842655&partnerID=8YFLogxK

U2 - 10.1046/j.1365-2125.1999.00029.x

DO - 10.1046/j.1365-2125.1999.00029.x

M3 - Article

C2 - 10510150

AN - SCOPUS:0032842655

VL - 48

SP - 382

EP - 387

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 3

ER -