Differential foetal development of the O- and N-demethylation of codeine and dextromethorphan in man

1. Codeine and dextromethorphan were N-demethylated in human foetal liver microsomes at high rates which were close to the activities in adult livers. In contrast, foetal liver microsomes did not catalyze the O-demethylation of these drugs at mid-gestation. 2. The metabolic data were in accordance with the absence of P450IID6 and the presence of P450 IIIA as determined by Western blotting with anti-human P450 IID6 (MAb 114/2) and anti-rat P450 IIIA (PCN 2-13-1/C2) monoclonal antibodies, respectively. 3. The inhibitory effects of midazolam and dehydroepiandrosterone support the contention that the N-demethylase is a human foetal form of the cytochrome P450 IIIA family. Consistent with this we found that blotting with the MAb PCN 2-13-1/C2, which recognizes an epitope specific for the P450 III family, correlated well with the N-demethylase activities.