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Kinetics and metabolism of cyclophosphamide in the isolated perfused rat liver. The metabolism of cyclophosphamide (CP) in the isolated perfused rat liver was investigated using an enzymatic assay and high-performance liquid chromatography (HPLC). Dialysate samples were analyzed by HPLC for metabolites arising from microsomal metabolism (CP-oxazaphosphorine, carboxyphosphamide, phosphoramide mustard) and from direct conjugation with glutathione (CP-glutathione, N4-CP-glutathione). The perfused rat liver efficiently metabolized CP and converted it to one or more metabolites, mainly CP-glutathione, within 1 min of infusion. Only 30% of the infused CP could be recovered in the bile within 15 min. The formation rate of CP-glutathione was reduced by 80% by inhibiting the hepatic perfusion with metyrapone and by 90% by preincubating the liver with a mixture of glutathione depleting agents (diethylmaleate, p-nitrobenzyl-1,2-diamine). The addition of 50 microM dicoumarol (an inhibitor of epoxide hydrolase) further decreased the formation of CP-glutathione from 35 to 16 nmol/min per g liver. The microsomal fraction was shown to catalyze the hydrolysis of CP-glutathione, thus releasing phosphoramide mustard and oxazaphosphorine. The results of the present study confirm the presence of several toxic metabolites (oxazaphosphorine, phosphoramide mustard) of CP in perfusates and bile. The formation of oxazaphosphorine and phosphoramide mustard is catalyzed by the hepatic microsomal fraction. The major metabolic pathway of CP in the rat liver involves glutathione conjugation. The lack of CP-oxazaphosphorine formation indicates that an additional detoxification pathway is operative in the intact liver. This observation, coupled with the limited excretion of CP-glutathione into the bile and its intracellular hydrolysis, suggests that CP is eliminated mainly by biliary excretion. The role of nonenzymatic hydrolysis of the CP-glutathione conjugate is also described. The implications of the present results for the design of clinical studies are discussed.