Metabolic pathways and pharmacokinetics of BOF-4272, a sulfoxide-containing drug, in the dog: in vivo and in vitro studies.
BOF-4272, (+/-)-8-(3-methoxy-4- phenylsulfinylphenyl)pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one, is a new drug intended for the treatment of hyperuricemia. This report describes the detailed metabolic pathways of BOF-4272 in the dog. The metabolic pathways were investigated using the metabolites found in plasma, urine, and feces after intravenous or oral administration of BOF-4272, as well as the metabolites found in the liver S9 incubation mixture after the addition of BOF-4272 or BOF-4269. BOF-4269 (the sulfide metabolite of BOF-4272) was the only metabolite detected in plasma and feces after the intravenous or oral administration of BOF-4272. BOF-4269 was detected in dog plasma after a lag time following the oral administration of BOF-4272, and the Cmax and AUC0-t of BOF-4269 were higher in fed dogs than in fasted dogs after the oral administration of BOF-4272. A small amount of BOF-4269 was detected in dog plasma immediately after the intravenous administration of BOF-4272. Only BOF-4276 (the sulfone metabolite of BOF-4272) was detected in the S9 incubation mixture after the addition of BOF-4272. Mainly BOF-4272 was detected and small amounts of BOF-4276 and M-1 (the hydroxy metabolite of BOF-4269) were detected in the S9 incubation mixture after the addition of BOF-4269. These findings suggest that BOF-4272 is mainly metabolized to BOF-4269 by the intestinal flora in dogs, whereas little of this drug is metabolized to BOF-4269 in the dog liver. In conclusion, this work has allowed us to formulate the proposed metabolic pathways of BOF-4272 in the dog.
Naito
S
S
Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan.
Nishimura
M
M
Yoshitsugu
H
H
Nogawa
H
H
D000818:Animals; D001711:Biotransformation; D004285:Dogs; D004791:Enzyme Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D005243:Feces / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D008297:Male; D013454:Sulfoxides / Q000737:chemistry / Q000494:pharmacology; D014227:Triazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine
D004791:Enzyme Inhibitors; D013454:Sulfoxides; D014227:Triazines; C072977:BOF 4272