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Cancer Chemother Pharmacol. 2003 Aug;52(2):139-46. Epub 2003 May 22. Related
Articles, Links
Biliary excretion of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) and
metabolites by Fischer 344 rats.
Musser SM, Egorin MJ, Zuhowski EG, Hamburger DR, Parise RA, Covey JM, White KD,
Eiseman JL.
Instrumentation and Biophysics Branch, Center for Food Safety and Applied
Nutrition, Food and Drug Administration, College Park, MD 20740, USA.
PURPOSE: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), an analogue of the
benzoquinone ansamycin geldanamycin, has been extensively studied preclinically
and is being evaluated clinically. Studies were performed to define the biliary
excretion of 17AAG after i.v. delivery to rats, and to characterize the
metabolites of 17AAG observed in rat bile. MATERIALS AND METHODS: In vivo
studies were performed in bile-duct-cannulated Fischer 344 rats given a 10 mg/kg
i.v. bolus dose of 17AAG. In vitro studies were performed with cloned human CYPs
and microsomal epoxide hydrolase. Biliary excretion of 17AAG and metabolites was
quantified by HPLC and followed for 4 h after drug delivery. 17AAG metabolites
in bile and in in vitro reaction mixtures were identified with LC/MS/MS.
RESULTS: By 15 min after i.v. delivery of 17AAG, bile contained at least 15
biotransformation products with absorbance spectra similar to that of 17AAG. Of
these, metabolites eluting at 2.7, 2.9, and 8.6 min were present in sufficient
concentrations to be quantified, although the lack of authentic standards
resulted in their being expressed as 17AAG equivalents. Within the first 4 h
after drug delivery, biliary excretion accounted for 28.9+/-6.1% of the 10-mg/kg
17AAG dose. 17AAG and 17-(amino)-17-demethoxygeldanamycin (17AG) accounted for
4.1+/-1.0% of the delivered dose, with 17AAG accounting for 2.0+/-0.5% and 17AG
accounting for 2.1+/-0.5%. The metabolites eluting at 2.7, 2.9, and 8.6 min
accounted for 10.6+/-2.0%, 9.8+/-1.2%, and 1.0+/-0.2%, respectively, of the
administered dose. LC/MS/MS analysis of bile demonstrated major metabolites with
molecular weights of 545 and 619, corresponding to 17AG and the diol previously
described as resulting from metabolism of 17AAG by CYP3A and microsomal epoxide
hydrolase. Of the remaining proposed metabolites, ten had a mass and MS/MS
spectrum consistent with mono-oxygenated 17AAG metabolites. One of these
metabolites has been identified as the epoxide previously described as resulting
from CYP3A oxidation of the allyl double bond. Two other proposed metabolites
had a mass and MS/MS spectrum consistent with demethylated 17AAG metabolites,
and one had a mass and MS/MS spectrum consistent with a di-demethylated 17AAG
metabolite. An analogous series of demethylated and oxidized metabolites was
also observed for the 17AG metabolite. CONCLUSIONS: Biliary excretion of 17AAG
represents a major route of elimination, although most of the material excreted
is in the form of metabolites. Bile of rats dosed with 17AAG contained a number
of metabolites not previously identified in the plasma or urine of mice treated
with 17AAG, but analogous to metabolites described in bile of rats treated with
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG, NSC 707545),
another geldanamycin analogue undergoing preclinical evaluation in preparation
for subsequent clinical trials.
PMID: 12761648
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