title: Pharmacokinetics, metabolism, and disposition of rivoglitazone, a novel peroxisome proliferator-activated receptor γ agonist, in rats and monkeys.
abstract: The pharmacokinetics, metabolism, and excretion of rivoglitazone [(RS)-5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzyl}-1,3-thiazolidine-2,4-dione monohydrochloride], a novel thiazolidinedione (TZD) peroxisome proliferator-activated receptor γ selective agonist, were evaluated in male F344/DuCrlCrlj rats and cynomolgus monkeys. The total body clearance and volume of distribution of rivoglitazone were low in both animals (0.329-0.333 ml per min/kg and 0.125-0.131 l/kg for rats and 0.310-0.371 ml per min/kg and 0.138-0.166 l/kg for monkeys), and the plasma half-life was 4.55 to 4.84 h for rats and 6.21 to 6.79 h for monkeys. The oral bioavailability was high (>95% in rats and >76.1% in monkeys), and the exposure increased dose proportionally. After administration of [(14)C]rivoglitazone, radioactivity was mainly excreted in feces in rats, whereas radioactivity was excreted in urine and feces with the same ratio in monkeys. Because excreted rivoglitazone in urine and bile was low, metabolism was predicted to be the main contributor to total body clearance. The structures of 20 metabolites (M1-M20) were identified, and 5 initial metabolic pathways were proposed: O-demethylation, TZD ring opening, N-glucuronidation, N-demethylation, and TZD ring hydroxylation. O-Demethylation was the main metabolic pathway in both animals, but N-demethylation and TZD ring hydroxylation were observed only in monkeys. N-Glucuronide (M13) was nonenzymatically hydrolyzed to TZD ring-opened N-glucuronide (M9), and the amount of these metabolites in monkeys was larger than that in rats. In plasma, rivolitazone was observed as the main component in both animals, and O-demethyl-O-sulfate (M11) was observed as the major metabolite in rats but as many minor metabolites in monkeys.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan. uchiyama.minoru.fe@daiichisankyo.co.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Haruo
authors.initials: H
authors.lastname: Iwabuchi
authors.forename: Fujiko
authors.initials: F
authors.lastname: Tsuruta
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.forename: Makoto
authors.initials: M
authors.lastname: Takahashi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Koda
authors.forename: Minoru
authors.initials: M
authors.lastname: Oguchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Okazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; C521549:rivoglitazone