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Evidence for a role of cytochrome P450 2D6 and 3A4 in ethylmorphine metabolism.
Author(s) -
Liu Z,
Mortimer O,
Smith CA,
Wolf CR,
Rane A
Publication year - 1995
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1995.tb04413.x
Subject(s) - ethylmorphine , dextromethorphan , quinidine , microsome , cyp3a4 , demethylation , cytochrome p450 , cyp2d6 , pharmacology , chemistry , biology , metabolism , biochemistry , in vitro , gene expression , dna methylation , gene
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.