Xenobiotica. 1991 Nov;21(11):1501-9.  

Thebaine O-demethylation to oripavine: genetic differences between two rat
strains.

Mikus G, Somogyi AA, Bochner F, Eichelbaum M.

Department of Clinical and Experimental Pharmacology, University of Adelaide,
Australia.

1. Codeine O-demethylation to morphine is mediated by cytochrome P450 IID1
(rat), or P450 IID6 (man), and exhibits genetic polymorphism. Thebaine is a
precursor in the formation of endogenous morphine and codeine in man, being
O-demethylated to oripavine. 2. The objective of the present study was to
ascertain whether the O-demethylation of thebaine to oripavine was mediated by
cytochrome P450 IID1 in rat liver microsomes. 3. Thebaine O-demethylation showed
strain differences in female Sprague-Dawley (SD) and female Dark-Agouti (DA)
rats, which serve as a model for the human debrisoquine/sparteine metabolism
phenotypes. 4. The total intrinsic clearance of thebaine to oripavine was high
(19.7 ml/h per mg protein) in SD rats, indicating that oripavine is a major
metabolite of thebaine. A 3-fold lower intrinsic clearance was observed in DA
rats (6.7 ml/h per mg protein). 5. Thebaine O-demethylation was inhibited by
quinine and known substrates of cytochrome P450 IID1/P450 IID6, supporting the
major involvement of cytochrome P450 IID1 in oripavine formation in rats.

PMID: 1763524 [PubMed - indexed for MEDLINE]