RT Journal Article
SR Electronic
T1 Human Biotransformation of Bropirimine
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1048
OP 1051
VO 26
IS 10
A1 Michael A. Wynalda
A1 Michael J. Hauer
A1 Larry C. Wienkers
YR 1998
UL http://dmd.aspetjournals.org/content/26/10/1048.abstract
AB Bropirimine (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a member of a class of antineoplastic agents known as aryl pyrimidinones. In human liver microsomal incubations, bropirimine oxidative metabolism is characterized by the formation of three metabolites. Mass spectrometric analysis of the incubation mixture revealed three bropirimine oxidative metabolites, identified as the bropirimine dihydrodiol,p-hydroxybropirimine, and m-hydroxybropirimine.In vitro studies using human liver microsomes and recombinant cytochrome P450 isoforms were performed to identify the P450 enzyme(s) responsible for bropirimine oxidation. Coincubation with the selective CYP1A2 inhibitor alpha-naphthoflavone abolished bropirimine metabolism in human liver microsomes. Furthermore, when screened against a panel of cDNA expressed cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), bropirimine was metabolized to both p- and m-hydroxybropirimine exclusively in incubations with cDNA-expressed CYP1A2 microsomes. Mechanistic studies using cDNA-expressed CYP1A2 microsomes fortified with microsomal epoxide hydrolase revealed that all three bropirimine oxidative metabolites appear to be the result of a common arene oxide, which serves as a substrate for microsomal epoxide hydrolase to generate the dihydrodiol or rearranges to yield p- andm-hydroxybropirimine. The American Society for Pharmacology and Experimental Therapeutics