Metabolism of 1-(3-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl)-3-(6-methoxypyridin-3-yl)-1-(2-trifluoromethylbenzyl)thiourea (YH3945), a novel anti-cancer drug, in rats using the 14C-labeled compound.
The metabolism of a novel anti-cancer agent, 1-(3-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-propyl)-3-(6-methoxypyridin-3-yl)-1-(2-trifluoromethylbenzyl)thiourea (YH3945), was investigated in rats. Bile, plasma, feces, and urine were collected and analyzed by a high-performance liquid chromatography (HPLC) system equipped with ultraviolet (UV), mass spectrometric, and radioactivity detectors. After intravenous dosing, mean radiocarbon recovery was 74.4 +/- 1.3% with 62.4 +/- 1.2% in the feces and 12.0 +/- 0.5% in the urine. Biliary excretion of the radioactivity for the first 24 h period was approximately 32%, suggesting that YH3945 is cleared by hepatobiliary excretion. YH3945 was extensively metabolized to 21 different metabolites including glucuronide conjugates, and structures of the metabolites were elucidated based on MS(n) and NMR spectral analyses. The major metabolic pathways in the rat were identified as O-demethylation of methoxypyridine, N-debenzylation of imidazole, and hydroxylation. Cyclic metabolites were also identified; concomitant demethylation in the methoxypyridine moiety and hydroxylation at the C16 position might destroy the chemical stability of the compound and subsequently lead to non-enzymatic cyclization. Cyclic metabolites were characteristic of YH3945, and a non-enzymatic reaction mechanism for the formation of cyclic metabolites was postulated.
Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Chungryang, Seoul 136-791, South Korea.
Jaeick
J
Lee
Sookie
S
La
Byung Rak
BR
Ahn
Tae Cheon
TC
Jeong
Dong-Hyun
DH
Kim
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; C492268:YH3945; D013890:Thiourea