Received for publication October 5, 2004.
Revised February 15, 2005.
Accepted for publication February 23, 2005.

The Distribution, Metabolism, and Elimination of Clofarabine in Rats

Abstract

The distribution, metabolism and elimination of intravenous 14C-clofarabine was studied in Fischer 344 male rats under a once daily for 5 days dosing schedule of 25 or 50 mg/kg/day. Also, the in vitro metabolism in rat, dog, and human hepatocytes was studied. Plasma radioactivity (of which clofarabine accounted for 63% to 93%) exhibited three phases of exponential elimination with half-lives of 0.3, 1.3, and 12.8 hours after administration of the 25 mg/kg/d regimen. Unscheduled deaths occurred after 1 to 3 doses with the 50 mg/kg regimen, possibly due to nonlinear pharmacokinetics, and so mass balance and radiokinetic profiles could not be obtained. A total of 77.1% (of which 87.2% was clofarabine) and 10.8% (of which 6.9% was clofarabine) of the dose was recovered in urine and feces, respectively. 6-ketoclofarabine, believed to be formed via adenosine deaminase, was the metabolite of greatest concentration found in urine and feces, but in each matrix accounted for only 7% of the daily recovery of radioactivity. 6 ketoclofarabine was also found in myocardium and liver, but accounted for less than 2% of the total radioactivity in those tissues. Clofarabine was the major analyte found in myocardium (> 97% region of integration) and liver (> 94% region of integration). Whole body autoradiography demonstrated that the highest postdistributive concentrations of radioactivity were in the excretory organs, kidney, bladder and GI tract, with no remarkable suborgan distribution. In rat, dog, and human hepatocytes, 95, 96, and 99.8% [14C]-clofarabine remained, respectively, after 6 hours incubation. Eleven metabolites were observed with the largest constituting 2.5% of the radioactivity.

Key words: anticancer agents, hepatocytes, kinetic modeling, renal elimination

This article has been cited by other articles:

				K. M. King, V. L. Damaraju, M. F. Vickers, S. Y. Yao, T. Lang, T. E. Tackaberry, D. A. Mowles, A. M. L. Ng, J. D. Young, and C. E. Cass A Comparison of the Transportability, and Its Role in Cytotoxicity, of Clofarabine, Cladribine, and Fludarabine by Recombinant Human Nucleoside Transporters Produced in Three Model Expression Systems Mol. Pharmacol., January 1, 2006; 69(1): 346 - 353. [Abstract] [Full Text] [PDF]