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|Title:||Oxidative metabolism of dihydrocodeine in Dark- Agouti and Sprague-Dawley rat liver microsomes|
|Citation:||Pharmaceutical Sciences, 1996; 2(6):299-303|
|Publisher:||Royal Pharmaceutical Society of Great Britain|
|Lynette C. Kirkwood, Roger L. Nation, Geoffrey D. Reynolds, Andrew A. Somogyi and Lloyd N. Sansom|
|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 Km (943 μM for Dark-Agouti; 123 μM for Sprague-Dawley), Vmax (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 Af-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.|
|Rights:||© 1996 Pharmaceutical Sciences|
|Appears in Collections:||Pharmacology publications|
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