tanespimycin and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin

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.

Topics: Antineoplastic Agents; Benzoquinones; Biotransformation; Cytochrome P-450 Enzyme System; Drug Stability; Glutathione; Humans; In Vitro Techniques; Lactams, Macrocyclic; Metabolic Detoxication, Phase II; Microsomes, Liver; Models, Molecular; Oxidation-Reduction

Topics: Animals; Benzamides; Benzoquinones; Clinical Trials as Topic; Drug Design; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Molecular Structure; Purines; Resorcinols; Structure-Activity Relationship