RT Journal Article
SR Electronic
T1 In Vitro Metabolism of 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin in Human Liver Microsomes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 627
OP 635
DO 10.1124/dmd.110.036418
VO 39
IS 4
A1 Nan Zheng
A1 Peng Zou
A1 Shaomeng Wang
A1 Duxin Sun
YR 2011
UL http://dmd.aspetjournals.org/content/39/4/627.abstract
AB The objective of this study was to investigate the oxidative metabolism pathways of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), a geldanamycin (GA) derivative and 90-kDa heat shock protein 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 GSH. 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 metabolized primarily through the reduction of benzoquinone and GSH 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 cytochrome P450 isozymes involved in the oxidative metabolism of 17-DMAG, whereas CYP2C8, 2D6, 2A6, 2C19, and 1A2 made minor contributions to the formation of metabolites. On the basis of the identified metabolite profiles, the biotransformation pathways for 17-DMAG in HLMs were proposed.