1. Evidence for a role of cytochrome P450 2D6 and 3A4 in ethylmorphine metabolism
- Author
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Anders Rane, O. Mortimer, Zhurong Liu, C. R. Wolf, and C. A. D. Smith
- Subjects
Quinidine ,Adult ,Male ,Blotting, Western ,Biology ,Pharmacology ,Mixed Function Oxygenases ,Cytochrome P-450 Enzyme System ,Cytochrome P-450 CYP3A ,medicine ,Ethylmorphine ,Humans ,Pharmacology (medical) ,Chromatography, High Pressure Liquid ,CYP3A4 ,Cytochrome P450 ,Dextromethorphan ,Middle Aged ,Phenotype ,Cytochrome P-450 CYP2D6 ,Microsome ,biology.protein ,Microsomes, Liver ,Female ,medicine.drug ,Research Article - Abstract
Ethylmorphine is metabolised by N-demethylation (to norethylmorphine) and by O-deethylation (to morphine). The O-deethylation reaction was previously shown in vivo to co-segregate with the O-demethylation of dextromethorphan indicating that ethylmorphine is a substrate of polymorphic cytochrome P450(CYP)2D6. To study further the features of ethylmorphine metabolism we investigated its N-demethylation and O-deethylation in human liver microsomes from eight extensive (EM) and one poor metaboliser (PM) of dextromethorphan. Whereas N-demethylation varied only two-fold there was a 4.3-fold variation in the O-deethylation of ethylmorphine, the lowest rate being observed in the PM. Quinidine, at a concentration of 1 microM, inhibited O-deethylation in microsomes from an EM, but was unable to do so in microsomes from the PM. The immunoidentified CYP2D6 and CYP3A4 correlated with the rates of O-deethylation (r = 0.972) and N-demethylation (r = 0.969), respectively. We conclude that the O-deethylation of ethylmorphine is catalysed by the CYP2D6 in human liver microsomes consistent with previous findings in healthy volunteers.
- Published
- 1995