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Cancer Chemother Pharmacol. 2002 Jan;49(1):7-19 Pharmacokinetics,
tissue distribution, and metabolism of
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in
CD2F1 mice and Fischer 344 rats
Egorin MJ, Lagattuta TF, Hamburger DR, Covey JM, White KD, Musser SM,
Eiseman JL
PURPOSE:
17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG) is an
analogue of the benzoquinone ansamycin compound
17-(allylamino)-17-demethoxygeldanamycin (17AAG), which is currently
being evaluated in clinical trials. Studies were performed in mice and
rats to: (1) define the plasma pharmacokinetics, tissue distribution,
and urinary excretion of 17DMAG after i.v. delivery; (2) define the
bioavailability of 17DMAG after i.p. and oral delivery; (3) characterize
the biliary excretion of 17DMAG after i.v. delivery to rats; and (4)
characterize, if possible, any metabolites of 17DMAG observed in plasma,
tissue, urine, or bile.
MATERIALS AND METHODS:
Studies were performed in female, CD2F1 mice or male Fischer 344
rats. In preliminary toxicity studies and subsequent i.v.
pharmacokinetic studies in mice, 17DMAG i.v. bolus doses of 33.3, 50,
and 75 mg/kg were used. In bioavailability studies, i.p. and oral 17DMAG
doses of 75 mg/kg were used. In preliminary toxicity studies in rats,
i.v. bolus doses of 10 and 20 mg/kg were used, and in i.v.
pharmacokinetic studies 10 mg/kg was used. Compartmental and
noncompartmental analyses were applied to the plasma concentration
versus time data. In mice and rats, concentrations of 17DMAG were
determined in multiple tissues. Urine was collected from mice and rats
treated with each of the i.v. doses of 17DMAG mentioned above, and drug
excretion was calculated until 24 h after treatment. Biliary excretion
of 17DMAG and metabolites was studied in bile duct-cannulated rats given
a 10 mg/kg i.v. bolus dose of 17DMAG. 17DMAG metabolites were identified
with LC/MS. RESULTS:
A 75 mg/kg dose of 17DMAG caused no changes in appearance, appetite,
waste elimination, or survival of treated mice as compared to
vehicle-treated controls. Bolus i.v. delivery of 17DMAG at 75 mg/kg
produced "peak" plasma 17DMAG concentrations between 18 and 24.2
microg/ml in mice killed at 5 min after injection. Sequential reduction
in the 17DMAG dose to 50 and 33.3 mg/kg resulted in "peak" plasma 17DMAG
concentrations between 9.4 and 14.4, and 8.4 and 10.5 microg/ml,
respectively. Plasma 17DMAG AUC increased from 362 to 674 and 1150
microg/ml x min when the 17DMAG dose increased from 33.3 to 50 and 75
mg/kg, respectively, corresponding to a decrease in 17DMAG CLtb from 92
ml/min per kg to 75 and 65 ml/min per kg. Plasma 17DMAG concentration
versus time data were best fit by a two-compartment open linear model.
No potential 17DMAG metabolites were observed in plasma. 17DMAG
bioavailability was 100% and 50% after i.p. and oral delivery,
respectively. In rats, an i.v. bolus dose of 10 mg/kg produced peak
plasma 17DMAG concentrations between 0.88 and 1.74 microg/ml. Plasma
17DMAG concentrations had fallen below the lower limit of quantitation
by 180 min and were best fit by a one-compartment open linear model. The
plasma 17DMAG AUC was 104 microg/ml x min, corresponding to a 17DMAG
CLtb of 96 ml/min per kg. 17DMAG distributed rapidly to all mouse and
rat tissues except brain and testes. Only mouse liver contained
materials consistent with potential metabolites of 17DMAG, but their
concentrations were below the limit of quantitation of the HPLC assay
used. Within the first 24 h after delivery, urinary excretion of 17DMAG
by mice and rats accounted for 10.6-14.8% and 12.5-16%, respectively, of
the delivered dose. By 15 min after i.v. delivery of 10 mg/kg of 17DMAG,
rat bile contained 11 new materials with absorbance similar to that of
17DMAG. Four of these proposed metabolites had an Mr of 633, indicating
addition of an oxygen. Two of these proposed metabolites had an Mr of
603, implying the loss of one methyl group, and one had an Mr of 589,
implying the loss of two methyl groups. The remaining four proposed
metabolites had an Mr of 566, 571, 629, and 645, respectively. Biliary
excretion of 17DMAG and metabolites accounted for 4.7 +/- 1.4% of the
delivered dose, with 17DMAG accounting for 50.7 +/- 3.4% of the biliary
excretion.
CONCLUSIONS:
17DMAG has excellent bioavailability when given i.p. and good
bioavailability when given orally. 17DMAG is widely distributed to
tissues and is quantitatively metabolized much less than is 17AAG. The
pharmacokinetic and metabolite data generated should prove relevant to
the design of additional preclinical studies as well as to contemplated
clinical trials of 17DMAG and could be useful in their interpretation.
PMID: 11855755 |
