Evidence for a role of cytochrome P450 2D6 and 3A4 in ethylmorphine metabolism.
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.
Liu
Z
Z
Department of Clinical Pharmacology, Akademiska Hospital, Uppsala University, Sweden.
Mortimer
O
O
Smith
C A
CA
Wolf
C R
CR
Rane
A
A
D000328:Adult; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism* / Q000502:physiology; D005036:Ethylmorphine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism* / Q000502:physiology; D010641:Phenotype
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005036:Ethylmorphine