Mannen Mishima

Metabolic fate of indometacin farnesil, a prodrug of indomethacin : characteristic biotransformation of indometacin farnesil in rats

1. Hydrolysis of indometacin farnesil (IMF), a farnesyl ester of indomethacin, was higher in plasma and pancreatic juice than in liver and kidney homogenates of rats. Plasma hydrolytic activity was extremely low in beagle dog, monkey and human. 2. Orally administered 14C-IMF was absorbed mainly via the throacic lymph duct and distributed into tissues such as liver, adrenal and spleen as the unchanged from; the 14C in rat plasma was present mainly as indomethacin released from IMF. 3. The concentration ratios of indomethacin in carrageenin-induced inflamed paw to blood after 14C-IMF administration were significantly greater than those after 14C-indomethacin dosing. 4. These results indicate that absorbed IMF might be transported as the unchanged drug into tissues, including the site of inflammation and then hydrolysed to indomethacin in the tissues.

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.

Absorption, distribution, metabolism and excretion of a new, 14C-labelled oxazolidinone MAO-A inhibitor in rat and dog.

1. After oral administration of 14C-labelled (5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-metho xymethyl -2-oxazolidinone (E2011) at a dose of 1 mg/kg, the blood level of radioactivity reached a maximum concentration (Cmax) of 0.545 microgram eq./ml after 0.25 h in the rat and of 0.900 microgram eq./ml after 0.5 h in the dog. In dog plasma, Cmax for radioactivity and unchanged E2011 were 0.862 microgram eq./ml and 0.650 microgram/ml respectively with corresponding Tmax (time at Cmax) of 0.75 and 0.25 h. The unchanged drug in dog plasma was below the detection limit (5 ng/ml plasma) after 24 h. 2. The tissue levels of radioactivity were measured at 0.25 (Tmax), 6, 24, and 168 h after administration to the rat and at 0.5 (Tmax), 24, and 168 h in the dog. The radioactivity was distributed in all tissues examined at Tmax in the rat and dog. The radioactivity levels of the cerebral cortex in the rat and dog were 26 and 36% of the plasma level at Tmax. The radioactivity in tissues decreased at almost the same rate as that in plasma. Plasma protein binding of the unchanged drug in the rat in vitro were about 70% in the range of 0.1-10 micrograms/ml, and those in the dog were about 45% in the same concentration range. 3. Cumulative excretion of radioactivity in the rat was 74.5% in urine and 22.5% in faeces after 7 days. In the dog, 55.5 and 36.5% of the radioactivity administered were excreted in urine and faeces respectively after 7 days. The biliary excretion of radioactivity in the cannulated rat was 23.0% within 48 h. 4. In tlc analysis of plasma and tissues of the rat and dog, the radioactivity for the unchanged drug was much higher than metabolites. In tlc analysis of urine, the same metabolites were detected in the rat and dog, and the radioactivity of a metabolite, IM1, was the highest in the both animals. Eight metabolites were detected in the plasma, tissues and excreta of the rat, and four metabolites in the dog. 5. In conclusion, the absorption, distribution, metabolism and excretion of 14C-labelled E2011 in the rat and dog have been established, and only minor differences were observed between these species.