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Shaw LM , Bonner HS , Brown DQ
Metabolic Pathways of Wr-2721 (Ethyol, Amifostine) in the Balb/C Mouse
Drug Metabolism and Disposition. 1994 Nov-Dec;22(6) :895-902
PMID: ISI:A1994PV16300013   
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This study investigated the metabolism of the radio- and chemoprotector compound, WR-2721 [amifostine; s-2-(3- aminopropylamino)ethylphosphorothioate], in the Balb/c mouse. The latter was selected for these studies because considerable radiation protection data have been published for this mouse strain using the WR-2721 dose, route of administration, and optimal time for protection following intraperitoneal injection used herein. It is known that protection requires conversion of the parent drug to its free thiol metabolite, WR-1065, in cultured cells. Because it is possible that metabolites of WR- 1065 could be involved in protection and because thiols are metabolically very reactive molecules, we investigated the metabolism of WR-2721 using electrochemical detection-HPLC methods. The following are the major findings in this study: I)WR-2721 drug was rapidly cleared from the bloodstream. Blood concentration of the parent drug decreased 10-fold 30 min after administration from the maximal observed value at 5 min 2) WR- 1065 rapidly appeared in the perchloric acid (PCA) soluble fraction of normal solid tissues. The highest WR-1065 concentrations in liver and kidney were 965 and 2195 mu mol/kg, respectively, 10 min after parent drug administration, whereas for heart and small intestine the highest values were 739 and 410 mu mol/kg at 30 min. 3) WR-1065 accumulated in the PCA- soluble fraction of two experimental tumors at a lower rate than for the other tissues. 4) In addition to WR-1065, we identified the following as metabolites of the parent drug present in the PCA-soluble fraction of the tissues examined: WR-33278, the symmetrical disulfide of WR-1065; the mixed disulfides WR-1065-cysteine and WR-1065-GSH; and cysteamine. 5) A significant fraction (78%) of radioactivity derived from administered [C-14]WR-2721 in blood was associated with the PCA-insoluble fraction, presumably bound to soluble and membrane proteins via [C-14]WR-1065 mixed disulfides. 6) Contrary to studies in other mouse species that showed that WR- 2721 administration led to a decrease in glutathione concentration in liver tissue, WR-2721 administration did not cause a reduction of glutathione concentration in either liver or kidney, but there was a 50% decrease in blood, 30 min after drug administration-a time point at which optimal radiation protection has been observed for this mouse strain.