Abstract
The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin (GA) derivative and Hsp90 inhibitor. In vitro metabolic profiles of 17-DMAG were examined by using pooled human liver microsomes (HLMs) and recombinant CYP450 isozymes in the presence or absence of reduced glutathione. In addition to 17-DMAG hydroquinone and 19-glutathionyl 17-DMAG, several oxidative metabolites of 17-DMAG were detected and characterized by liquid chromatography-tandem mass spectrometry. Different from previously reported primary biotransformations of GA and GA derivatives, 17-DMAG was not primarily metabolized through the reduction of benzoquinone and glutathione conjugation in HLMs. In contrast, the primary biotransformations of 17-DMAG in HLMs were hydroxylation and demethylation on its side chains. The most abundant metabolite was produced by demethylation from the methoxyl at position 12. The reaction phenotyping study showed that CYP3A4 and 3A5 were the major P450 isozymes involved in the oxidative metabolism of 17-DMAG while CYP 2C8, 2D6 2A6, 2C19 and 1A2 made minor contributions to the formation of metabolites. Based on the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed.
- Received September 23, 2010.
- Accepted December 22, 2010.
- The American Society for Pharmacology and Experimental Therapeutics