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Aldofosfamide-perhydrothiazine derivatives are a new class of prodrugs which spontaneously, with half-life times of 2 to12 h hydrolyse to the corresponding aldophosphamide in aquous solution. Synthesis of 1-aldofosfamide-perhydrothiazine (N,N'-(2-chloroethyl)-phosphorodiamide-2-(2'-[4'-carboxy-1',3'- perhydrothiazinyl])-ethylester) and a derivative, in which one 2-chlorethyl group of the alkylating function is substituted by a mesyl-ethyl-group (N-(2-Chloroethyl)-N'-(methanesulphonylethyl)- phosphorodiamide-2-(2'-[4'-carboxy-1',3'-perhydro-thiazinyl] )-ethylester), is described.

The experimental and pharmacokinetic basis for the local chemotherapy of body cavities with 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stable derivative of activated cyclophosphamide (CP), was evaluated on the S 180 ascites sarcoma in mice. The severe local toxicity of P1 observed after intraperitoneal administration was markedly reduced by increasing the injection volume (belly bath) without significant loss of cytotoxic activity on the S 180 tumor. Simultaneous application of L-cysteine as a "protector thiol" resulted in further reduction of toxicity without significantly decreasing the cytotoxic effect on tumor cells. Thus the therapeutic index was increased (2.5 fold) by the combination of belly bath and protection by L-cysteine, contrary to 2-mercaptoethane sulfonic acid sodium salt (Mesna) as protector thiol which reduced both the acute toxicity and the curative effectiveness of P1. Pharmacokinetic parameters were determined by measuring the concentrations of P1 and 4-hydroxycyclophosphamide (4-OH-CP), carboxyphosphamide and 4-ketocyclophosphamide in blood and peritoneal fluid. As a result of these measurements the reduction of toxicity of P1 after high volume i.p. administration is due to increased enzymatic detoxification of 4-OH-CP to 4-ketocyclophosphamide and carboxyphosphamide. The effect of L-cysteine on the toxicity of P1 is mainly the consequence of transmercaptalisation of P1 to 4-(S-cysteine)-sulfido-CP. By this reaction formation of the toxic 4-OH-CP in the peritoneal cavity is diminished, and the peritoneal clearance of "activated" CP reduced.

Patients with impaired liver function have a reduced biotransformation rate of the cytostatic agent cyclophosphamide. With pathologically reduced serum cholinesterase activity the half-life of the drug increases from normally 4.3 h to 6.7 h. These patients show significantly lower peak levels of activated cyclophosphamide (4-hydroxy-cyclophosphamide + aldophosphamide). Because of the low renal clearance of cyclophosphamide (16 ml/min) and equally low renal excretion of activated cyclophosphamide amounting to only 1% of the applied dose more than 80% of the drug is still metabolized and the area under the curve of activated cyclophosphamide (cXt) remains relatively constant. No change in the pharmacokinetics of cyclophosphamide and its activated metabolite is observed in an anuric patient. However, an accumulation of toxic, directly alkylating metabolites with a fourfold alkylation rate of plasma proteins is found in this case. Hemodialysis sufficiently eliminated the toxic alkylating metabolites without a measurable influence on the pharmacokinetics of activated cyclophosphamide.