Stereoselective metabolism of conformational analogs of warfarin by .beta.-naphthoflavone-inducible cytochrome P-450

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Abstract
Previous studies showed that the structurally related oral anticoagulants warfarin and phenprocoumon are regioselectively hydroxylated in the 6- and 8-positions by hepatic microsomes obtained from 3-methylcholanthrene (3-MC) or .beta.-naphthoflavone (BNF) pretreated rats. Stereoselectivity for hydroxylation is also observed and favors (R)-warfarin but (S)-phenprocoumon. The possibility that the stereoselectivity of warfarin hydroxylation is a function of the solution conformation of the drug was tested with conformationally restricted analog. The analogs were incubated with microsomes obtained from BNF-pretreated rats and any stereoselectivity associated with 6- and 8-hydroxylation was determined. The R enantiomer of cyclocoumarol, the cyclic ketal analog of warfarin, was selectively hydroxylated, in contrast to the S enantiomer of warfarin 4-methyl ether, the ring-opened analog. The latter compound has a preferred solution conformation similar to that of phenprocoumon. At the active site of BNF-induced cytochrome P-450, (R)-warfarin is metabolized in its cyclic hemiketal tautomer, a form which spatially mimics the preferred solution conformation of (S)-phenprocoumon.