title: Thebaine O-demethylation to oripavine: genetic differences between two rat strains.
abstract: 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.
authors.affiliation: Department of Clinical and Experimental Pharmacology, University of Adelaide, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Mikus
authors.forename: A A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: F
authors.initials: F
authors.lastname: Bochner
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
mesh_terms: D000818:Animals; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013797:Thebaine / Q000031:analogs & derivatives* / Q000378:metabolism*
chemical_list: D013797:Thebaine; C005283:oripavine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6