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

Br J Clin Pharmacol. 1991 Sep;32(3):295-302. doi: 10.1111/j.1365-2125.1991.tb03902.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal
  • Blotting, Western
  • Chromatography, High Pressure Liquid
  • Codeine / metabolism*
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 Enzyme System / metabolism
  • Dehydroepiandrosterone / pharmacology
  • Dextromethorphan / metabolism*
  • Embryonic and Fetal Development*
  • Humans
  • Methylation
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Midazolam / pharmacology
  • Mixed Function Oxygenases / metabolism

Substances

  • Antibodies, Monoclonal
  • Dehydroepiandrosterone
  • Dextromethorphan
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Cytochrome P-450 CYP2D6
  • Codeine
  • Midazolam