Pharmacokinetics and tissue distribution of halofuginone (NSC 713205) in CD2F1 mice and Fischer 344 rats

Citation
Kp. Stecklair et al., Pharmacokinetics and tissue distribution of halofuginone (NSC 713205) in CD2F1 mice and Fischer 344 rats, CANC CHEMOT, 48(5), 2001, pp. 375-382
Citations number
39
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Issue
5
Year of publication
2001
Pages
375 - 382
Database
ISI
SICI code
0344-5704(200111)48:5<375:PATDOH>2.0.ZU;2-C
Abstract
Purpose: Halofuginone (HF) inhibits synthesis of collagen type I and matrix metalloproteinase-2 and is being considered for clinical evaluation as an antineoplastic agent. Pharmacokinetic studies were performed in rodents to define the plasma pharmacokinetics, tissue distribution, and urinary excret ion of HF after i.v. delivery and the bioavailability of HF after Lp. and o ral delivery. Materials and methods: Studies were performed in CD2F1 mice a nd Fischer 344 rats. In preliminary toxicity studies in mice single HF i.v. bolus doses between 1.0 and 5.0 mg/kg were used. Pharmacokinetic studies w ere conducted in mice after administration of 1.5 mg/kg HF. In preliminary toxicity studies in male rats HF i.v. bolus doses between 0.75 and 4.5 mg/k g were used. In pharmacokinetic studies in rats an HF dose of 3.0 mg/kg was used. Compartmental and non-compartmental analyses were applied to the pla sma concentration versus time data. Plasma, red blood cells, various organs , and urine were collected for analysis. Results: HF doses greater than or equal to1.5 mg/kg proved excessively toxic to mice. In mice, Lv. bolus deli very of 1.5 mg/kg HF produced "peak" plasma HF concentrations between 313 a nd 386 ng/ml, and an AUC of 19,874 ng/ml-min, which corresponded to a total body clearance (CLtb) of 75 ml/min per kg. Plasma HF concentration versus time data were best fit by a two-compartment open linear model. The bioavai lability of HF after i.p. and oral delivery to mice was 100% and 0%, respec tively. After i.v. bolus delivery to mice, HF distributed rapidly to all ti ssues, except brain. HF persisted in lung, liver, kidney, spleen, and skele tal muscle longer than in plasma. In the oral study, HF was undetectable in plasma and red blood cells, but was easily detectable in kidney, liver, an d lung, and persisted in those tissues for 48 h. Urinary excretion of HF ac counted for 7-11 % of the administered dose within the first 72 h after i.v . dosing and 15-16% and 16% of the administered dose within 24 and 48 h, re spectively, after oral dosing. There were no observed metabolites of HF in mouse plasma or tissues. In rats, i.v. bolus delivery of 3.0 mg/kg produced a "peak" plasma HF concentration of 348 ng/ml, and an AUC of 43,946 ng/ml- min, which corresponded to a CLtb of 68 ml/min per kg. Plasma HF concentrat ion versus time data were best fit by a two-compartment open linear model. After i.v. bolus delivery to rats, HF distributed rapidly to all tissues, w ith low concentrations detectable in brain and testes. HF was detectable in some tissues for up to 48 h. HF could be detected in rat plasma after a 3 mg/kg oral dose. Peak HF concentration (34 ng/ml) occurred at 90 min, but H F concentrations were less than the lower limit of quantitation (LLQ) by 42 0 min. Urinary excretion of HF accounted for 8-11 % of the administered dos e within the first 48 h after i.v. dosing. No HF metabolites were detected in plasma, tissue, or urine. Conclusions: HF was rapidly and widely distrib uted to rodent tissues and was not converted to detectable metabolites. In mice, HF was 100% bioavailable when given i.p. but could not be detected in plasma after oral administration. suggesting limited oral bioavailability. However. substantial concentrations were present In liver. kidney. and lun gs. HF was present in rat plasma after an oral dose. but the time course an d low concentrations achieved precluded reliable estimation of bioavailabil ity. These data may assist in designing and interpreting additional preclin ical and clinical studies of HF.