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 h after administration of the 25 mg/kg/day regimen. Unscheduled deaths occurred after one to three doses with the 50 mg/kg regimen, possibly due to nonlinear pharmacokinetics; therefore, 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, it 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 gastrointestinal tract, with no remarkable suborgan distribution. In rat, dog, and human hepatocytes, 95, 96, and 99.8% [¹⁴C]clofarabine remained, respectively, after 6 h of incubation. Eleven metabolites were observed, with the largest constituting 2.5% of the radioactivity.