title: Pharmacokinetic and pharmacodynamic properties of a novel xanthine oxidase inhibitor, BOF-4272, in healthy volunteers.
abstract: A novel pyrazolotriazine derivative [BOF-4272, sodium-(+-)-8-(3-methoxy-4-phenylsulfinylphenyl)pyrazolo[1,5-a]-1 ,3,5-triazine-4-olate monohydrate], which inhibits biosynthesis of uric acid (UA) by interfering with xanthine oxidase/xanthine dehydrogenase, was administered p.o. to healthy male volunteers to evaluate its pharmacokinetic and pharmacodynamic properties. In the single-dose study, three doses of BOF-4272 (100, 200 and 400 mg) and a placebo were allocated to eight subjects on three occasions at more than 1-week intervals in a single-blind and balanced incomplete block design. In the multiple-dose study, 200 mg of BOF-4272 and a placebo were administered to six and four subjects, respectively, twice daily for 6.5 days (13 total doses) in a single-blind design. Throughout the whole study period BOF-4272 was well tolerated in healthy subjects. In the single-dose study, the maximal plasma concentrations of BOF-4272 and its major metabolite (M-4) and their areas under the plasma concentration-time curve increased in proportion to the given dose. Both substances were eliminated from plasma with half-lives of 1.7 to 1.9 and 4.8 to 6.9 hr irrespective of the dose. BOF-4272 was recovered in the urine at about 1% as unchanged drug and 15% as M-4. In the single-dose study, serum UA concentration was decreased dose-dependently to about 80% of the predose value. In the multiple-dose study, serum UA concentration, which was measured before each morning dose, was decreased to about 72% on day 3 and maintained thereafter at almost the same level until 24 hr after the last administration.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Uematsu
authors.forename: M
authors.initials: M
authors.lastname: Nakashima
mesh_terms: D000328:Adult; D006207:Half-Life; D006801:Humans; D008297:Male; D012016:Reference Values; D014227:Triazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D014527:Uric Acid / Q000097:blood; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
chemical_list: D014227:Triazines; D014527:Uric Acid; C072977:BOF 4272; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase