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Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity
Y Caraco1, T Tateishi, F P Guengerich
1Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Summary
The study identified cytochrome P450 3A4 (CYP3A4) as the primary enzyme responsible for codeine N-demethylation to norcodeine. This finding is crucial for understanding drug interactions and predicting codeine
Area of Science:
- Pharmacology
- Drug Metabolism
- Enzymology
Background:
- Codeine undergoes metabolism via glucuronidation, O-demethylation to morphine by CYP2D6, and N-demethylation to norcodeine.
- The specific enzyme catalyzing codeine N-demethylation has not been definitively identified.
Purpose of the Study:
- To identify the specific cytochrome P450 (P450) enzyme responsible for the N-demethylation of codeine to norcodeine.
Main Methods:
- Human liver microsomes from 12 donors were incubated with codeine.
- Norcodeine formation was measured and correlated with activities of specific P450 enzymes.
- Inhibition studies were conducted using specific CYP3A4 inhibitors and antibodies.
Main Results:
- Codeine N-demethylation activity strongly correlated with nifedipine oxidation, a marker for CYP3A4.
- Selective CYP3A4 inhibitors (troleandomycin, gestodene, ketoconazole, erythromycin) significantly reduced norcodeine formation.
- Antibodies against CYP3A4 almost completely inhibited norcodeine production, while purified CYP3A4 demonstrated activity.
Conclusions:
- Cytochrome P450 3A4 (CYP3A4) is the principal enzyme responsible for codeine N-demethylation.
- Coadministration of codeine with CYP3A4 inhibitors may alter codeine metabolism, potentially increasing morphine levels and effects.