To separately assess intestinal and hepatic first-pass effects with absorption ratio data, we have established an experimental model of rats double-cannulated into the portal and jugular veins. The model allows us to take blood samples simultaneously from conscious rats that have recovered from surgical damage. Double cannulation did not alter the physiological and hematological conditions. Moreover, the plasma concentration profiles of unchanged drug following oral and intravenous administration in the double-cannulated rats were not different from those of rats single-cannulated into the jugular vein. These results suggest that the model can be useful for separately assessing intestinal and hepatic first-pass effects. We evaluated the first-pass effects in the intestine and the liver separately using this model. S-1452, as a model drug with 94% absorption ratio, was administered intravenously and orally to the double-cannulated rats, and the drug concentrations in the portal and systemic plasma were determined, and the rates of elimination from the intestine and liver were estimated. In the first pass, approximately 26% and 56% of the dose were extracted by the intestine and liver, respectively. This method, in which the animal is not restricted nor under anesthesia, allows us to obtain reliable values of individual first pass effects in the intestine and liver. This method can also be an effective tool for assessing the site and extent of drug-drug interaction on the first-pass effects.
[pivaloyl-14 C]S-1108, which is 14 C labeled at the pivalic acid moiety of the pivaloyloxymethyl side chain of S-1108, was administered orally to rats and dogs, and the disposition of pivalic acid cleft from S-1108 was examined. Besides pivaloylcarnitine and pivaloylglucuronide, pivaloylglycine was identified in dog urine as a metabolite of pivalic acid by thin-layer chromatography and high-performance liquid chromatography analysis. The concentrations in the plasma of rats to which doses of 6.65, 26.6, and 532 mg/kg of body weight were administered showed dose-proportionate levels. The radioactivity was eliminated rapidly, with a half-life of approximately 3 h until 24 h at both the 6.65-and 26.6-mg/kg doses. Free pivalic acid in plasma accounted for more than 80% of the concentration of radioactivity. Radioactivity was distributed throughout the body and was eliminated quickly at a rate similar to that of radioactivity from plasma. Most of the absorbed radioactivity was excreted in the urine, and it was completed within 24 h after administration. In dogs, the half-life of radioactivity in plasma was longer than that in the rats. The ratio of free pivalic acid in plasma was 60 to 70% of the radioactivity in plasma. The concentration of radioactivity in the liver, cortex of the kidney, and skeletal muscle 144 h after oral dosing was more than 10 times higher than the concentration in plasma for all doses. Urinary excretion in dogs was slower than that in rats. The differences in the disposition of pivalic acid between dogs and rats may account for differences in the degree of skeletal muscle disorders. The safety in humans of S-1108 given at 200 mg three times a day is discussed in relation to the metabolic formation of the carnitine conjugate of pivalic acid and the reduction of the carnitine concentration in plasma.S-1108 is a new oral cephem antibiotic and is a prodrug of S-1006 (12); the absorbability of S-1006 increases by esterification of the carboxy group at the C-4 position of the cephem ring with pivaloyloxymethyl (POM). S-1108 is hydrolyzed to the active moiety, S-1006, and components of the ester residue, formaldehyde and pivalic acid, by an esterase in the gut wall.
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