PHARMACOKINETICS OF THE ANTICANCER AGENT SULOFENUR IN MICE, RATS, MONKEYS, AND DOGS

The absorption and pharmacokinetics of sulofenur [N-(indan-5-sulfonyl) -N'-(4-chlorophenyl)urea, LY186641] and its major metabolites were exa mined in mice, rats, monkeys, and dogs. The compound is a diarylsutfon ylurea currently being evaluated as an oncolytic agent in phase I and II trials. In all species, sulofenur was well absorbed after an oral d ose, but over a prolonged period, and sulofenur exhibited a fairly lon g half-life of elimination from plasma. These values ranged from 6 h i n rats up to 30, 1 1 0, and 200 h in mice, monkeys, and dogs, respecti vely, at doses (240-1 000 mg/m2) within the range of those used in cli nical trials. Experiments describing the high degree of binding of sul ofenur to plasma proteins (consistently >99%) help to explain these re latively long half-lives. There is, however, a large difference betwee n these plasma half-lives in the species studied. Sulofenur was previo usly found to be extensively metabolized to products that are excreted primarily into the urine. In this study, its major metabolites, which are found mainly in the urine, were also minor components of the drug -related material (< 1 0% of the sulafenur concentrations) in the plas ma of rats treated with sulofenur. The absorption, binding characteris tics, and elimination of these major metabolites after their administr ation to rats were also compared with sulofenur. Comparison of the pha rmacokinetics of sulofenur with those of other well-studied sulfonylur eas of similar structure, which are metabolized in the same manner (mo st notably tolbutamide), suggests that for sulofenur as well, the grea t species difference in its plasma half-lives may be due to difference s in the rate of its oxidation to major metabolites.