Oxidative metabolism of dihydrocodeine in Dark-Agouti and Sprague-Dawley rat liver microsomes

L. C. Kirkwood, R. L. Nation, G. D. Reynolds, A. A. Somogyi, L. N. Sansom

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Abstract

The oxidative metabolism of dihydrocodeine to nordihydrocodeine and dihydromorphine was studied in liver microsomes of female Dark-Agouti (cytochrome P450 2D1 (CYP2D1) deficient) and Sprague-Dawley rats. Evaluation of microsomal metabolism in these two rat strains is a useful in-vitro model to test possible substrates of polymorphic human cytochrome P450 2D6 (CYP2D6). Nordihydrocodeine formation rates were similar in both strains. Analysis of the Michaelis-Menten kinetics of dihydromorphine formation showed a significant difference (P < 0.05) between strains with respect to K(m) (943 μM for Dark-Agouti; 123 μM for Sprague-Dawley), V(max) (0.925; 2.37 μmol min-1 g-1) and intrinsic clearance (0.986; 19.5 mL min-1 g-1). In Sprague-Dawley liver microsomes, dihydromorphine formation was suppressed by the CYP2D1 inhibitors, quinine and quinidine, at concentrations which had no effect on nordihydrocodeine formation. These in-vitro findings indicate that in rat liver microsomes the cytochrome P450 system is involved in dihydrocodeine metabolism to dihydromorphine and nordihydrocodeine and that CYP2D1 is involved in the O-demethylation to dihydromorphine but not the N-demethylation to nordihydrocodeine. The results of this study are in agreement with recent in-vivo studies of dihydrocodeine metabolism in man which indicate CYP2D6 is the predominant enzyme catalysing dihydromorphine formation.

Original languageEnglish
Pages (from-to)299-303
Number of pages5
JournalPharmaceutical Sciences
Volume2
Issue number6
Publication statusPublished - 1 Dec 1996

Cite this

Kirkwood, L. C., Nation, R. L., Reynolds, G. D., Somogyi, A. A., & Sansom, L. N. (1996). Oxidative metabolism of dihydrocodeine in Dark-Agouti and Sprague-Dawley rat liver microsomes. Pharmaceutical Sciences, 2(6), 299-303.
Kirkwood, L. C. ; Nation, R. L. ; Reynolds, G. D. ; Somogyi, A. A. ; Sansom, L. N. / Oxidative metabolism of dihydrocodeine in Dark-Agouti and Sprague-Dawley rat liver microsomes. In: Pharmaceutical Sciences. 1996 ; Vol. 2, No. 6. pp. 299-303.
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Kirkwood, LC, Nation, RL, Reynolds, GD, Somogyi, AA & Sansom, LN 1996, 'Oxidative metabolism of dihydrocodeine in Dark-Agouti and Sprague-Dawley rat liver microsomes', Pharmaceutical Sciences, vol. 2, no. 6, pp. 299-303.

Oxidative metabolism of dihydrocodeine in Dark-Agouti and Sprague-Dawley rat liver microsomes. / Kirkwood, L. C.; Nation, R. L.; Reynolds, G. D.; Somogyi, A. A.; Sansom, L. N.

In: Pharmaceutical Sciences, Vol. 2, No. 6, 01.12.1996, p. 299-303.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Oxidative metabolism of dihydrocodeine in Dark-Agouti and Sprague-Dawley rat liver microsomes

AU - Kirkwood, L. C.

AU - Nation, R. L.

AU - Reynolds, G. D.

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