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The diversity in xenobiotic metabolic pathways catalyzed by P450 or other drug-metabolizing enzymes is large.We often observe that xenobiotics are metabolized by unexpected and unusual pathways.In this presentation, we described two examples of novel drug metabolites.In the first example, we investigated an uncommon biotransformation of pyrimidineduring the metabolism of GNE-892, a secretase 1 inhibitor.Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the 14C-radiolabeled mass balance study in rats.Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance.This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide, which is followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate.After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazolering.In the second example, we described a novel cyclization reaction that was observed in the metabolism of GDC-0623, an orally bioavailable inhibitor of MEK1/2 investigated for treating solid tumors.