Kouzi Yamada

Inhibitory effect of indomethacin farnesil, a novel antiinflammatory prodrug, on carrageenin-induced inflammation in rats.

Antiinflammatory effects of indomethacin farnesil (IMF), a novel prodrug of indomethacin, was examined after both oral and local administration. In the air pouch carrageenin-induced inflammation, an oral dose of IMF exerted dose dependent inhibitory effects on the accumulation of inflammatory exudate fluid and the migration of leukocytes into the exudate. Both the increased vascular permeability and the prostaglandin E2 levels in the exudate fluid were reduced by IMF. Significant levels of free indomethacin were detected in the pouch fluid. In spite of the inability of IMF to inhibit prostaglandin synthesis in a cell free cyclooxygenase system, IMF injected locally inhibited carrageenin paw edema, and the inhibitory effect was comparable to that of indomethacin itself. When injected locally into the paw together with carrageenin,14C-IMF was effectively converted to its active metabolite, indomethacin. The indomethacin concentration in the paw tissue was comparable to that of indomethacin injected paws with the same molar dose of free indomethacin.

Identification of urinary and microsomal metabolites of geranylgeranylacetone in rats.

The metabolic disposition of the anti-ulcer agent geranylgeranylacetone (GGA) was examined in rats. Urinary metabolites were isolated and identified by mass spectrometry and 1H n.m.r. studies. Three metabolites were dicarboxylic acids with chain lengths of C7, C9 and C11 and accounted for 31.6%, 14.8% and 5.3%, respectively, of the radioactivity excreted in the urine 24 h after oral administration of 14C-GGA. The metabolites produced by the incubation of GGA with liver microsomes in the presence of an NADPH-generating system were identified as an omega-hydroxylated derivative of GGA and its ketone-reduced form. The characterization of GGA metabolites indicates that the metabolic pathway of GGA in rats involves omega-oxidation (possibly via the corresponding carboxylic acid) and successive beta-oxidation processes.

Metabolism and excretion of a new 5-lipoxygenase inhibitor in rats, guinea-pigs, beagles and rhesus monkeys.

1. The 5-lipoxygenase inhibitor (I), a substituted benzothiazole is metabolized mainly by glucuronide and/or sulphate conjugation in rat, guinea-pig, beagle and rhesus monkey. Glucuronidation is the major pathway, and sulphation is more extensive in rat and beagle than in guinea-pig and rhesus monkey. 2. After a single oral dosing of 14C-I (10 mg/kg), more than 96% of the dose was excreted in 7 days in all four species, however there is species difference in urinary excretion, which was 2.8 +/- 0.3% in rat, 46.9 +/- 1.6% in guinea-pig, 2.6% in beagle and 68.2% in rhesus monkey. 3. After a single i.v. dose of 14C-I to bile duct-cannulated rats and guinea pigs, bile was a major route of elimination, and in rats the ratio of glucuronide to sulphate in excreta increased from 0.71 +/- 0.01 to 0.93 +/- 0.05 as the dose was increased from 0.2 to 20 mg/kg.