Synthesis of 1-fluoro-substituted codeine derivatives
Syntheses of new N-demethyl-N-substituted analogues (propyl, allyl) of 1-fluorocodeine and their 7,8-dihydro derivatives were described starting from codeine. 1-Fluoronorcodeine and 1-fluorodihydronorcodeine were prepared by N-demethylation with α-chloroethyl chloroformate from the corresponding 6-O-acetyl protected derivatives. 3-O-Demethylation of 1-fluorocodeine and 1-fluorodihydrocodeine with boron tribromide resulted in 1-fluoromorphine and 1-fluorodihydromorphine respectively. 1-Fluorodihydromorphine was acetylated to 3,6-di-O-acetyl-1-fluorodihydromorphine. 8-Fluoroapocodeine and N-propyl-8-fluoroapocodeine were synthesized from the appropriate 1-fluorocodeine derivatives by acid-catalyzed rearrangement.
Oxidative metabolism of dihydrocodeine in Dark-Agouti and Sprague-Dawley rat liver microsomes
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 -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.
Kirkwood,Nation,Reynolds,Somogyi,Sansom
p. 299 - 303
(2007/10/03)
On the identification of dihydrocodeine phosphate and its preparations
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Asahina,Ono,Shimamine,Takahashi
p. 18 - 21
(2007/10/10)
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