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 examined in mice, rats, monkeys, and dogs. The compound is a diarylsulfonylurea currently being evaluated as an oncolytic agent in phase I and II trials. In all species, sulofenur was well absorbed after an oral dose, but over a prolonged period, and sulofenur exhibited a fairly long half-life of elimination from plasma. These values ranged from 6 h in rats up to 30, 110, and 200 h in mice, monkeys, and dogs, respectively, at doses (240-1000 mg/m2) within the range of those used in clinical trials. Experiments describing the high degree of binding of sulofenur to plasma proteins (consistently > 99%) help to explain these relatively long half-lives. There is, however, a large difference between these plasma half-lives in the species studied. Sulofenur was previously 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 (< 10% of the sulofenur concentrations) in the plasma of rats treated with sulofenur. The absorption, binding characteristics, and elimination of these major metabolites after their administration to rats were also compared with sulofenur.(ABSTRACT TRUNCATED AT 250 WORDS)
Ehlhardt
W J
WJ
Department of Drug Metabolism, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
Sullivan
H R
HR
Wood
P G
PG
Woodland
J M
JM
Hamilton
M
M
Hamilton
C
C
Cornpropst
D
D
Grindey
G B
GB
Worzalla
J F
JF
Bewley
J R
JR
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D005260:Female; D006207:Half-Life; D008253:Macaca mulatta; D051379:Mice; D008809:Mice, Inbred C3H; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013453:Sulfonylurea Compounds / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D001798:Blood Proteins; D013453:Sulfonylurea Compounds; C058179:sulofenur