Absorption, distribution, metabolism, and excretion of CKD-732, a novel antiangiogenic fumagillin derivative, in rats, mice, and dogs.
The pharmacokinetics of CKD-732 (6-O-4-[dimethyl-aminoethoxy)cinnamoyl]-fumagillol x hemioxalate) was investigated in male SD rats and beagle dogs after bolus intravenous administration. The parent compound and metabolites obtained from in vitro and in vivo samples were determined by LC/MS. The main metabolite was isolated and identified as an N-oxide form of CKD-732 by NMR and LC/MS/MS. CKD-732 was metabolized into either M11 or others by rapid hydroxylation, demethylation, and hydrolysis. The blood level following the intravenous route declined in first-order kinetics with T(1/2)beta values of 0.72 to approximately 0.78 h for CKD-732 and 0.92 to approximately 1.09 h for M11 in rats at a dose of 7.5 to approximately 30 mg/kg. In dogs, T(1/2)beta values of CKD-732 and M11 were 1.54 and 1.79 h, respectively. Moreover, AUC values increased dose dependently for CKD-732 and M11 in rats and dogs. The CLtot and Vdss did not change significantly with increasing dose, indicating linear pharmacokinetic patterns. The excretion patterns through the urine, bile, and feces were also examined in the animals. The total amount excreted in urine, bile, and feces was 2.13% for CKD-732 and 1.29% for M11 in rats, and 1.58% for CKD-732 and 2.28% for M11 in dogs.
Lee
Ho Sup
HS
Chong Kun Dang Research Institute, P.O. Box 74, Chonan 330-831, Korea.
Choi
Won Kyu
WK
Son
Hoe Joo
HJ
Lee
Sung Sook
SS
Kim
Joon Kyum
JK
Ahn
Soon Kil
SK
Hong
Chung Il
CI
Min
Hye-Ki
HK
Kim
Myungsoo
M
Myung
Seung-Woon
SW
D000042:Absorption; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002934:Cinnamates / Q000493:pharmacokinetics*; D003510:Cyclohexanes; D004285:Dogs; D004852:Epoxy Compounds / Q000493:pharmacokinetics*; D005231:Fatty Acids, Unsaturated / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000493:pharmacokinetics*; D013045:Species Specificity; D014018:Tissue Distribution
D020533:Angiogenesis Inhibitors; D002934:Cinnamates; D003510:Cyclohexanes; D004852:Epoxy Compounds; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; C487952:CKD732; D000077609:O-(Chloroacetylcarbamoyl)fumagillol