Wj. Ehlhardt et al., PHARMACOKINETICS OF THE ANTICANCER AGENT SULOFENUR IN MICE, RATS, MONKEYS, AND DOGS, Journal of pharmaceutical sciences, 82(7), 1993, pp. 683-688
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.