[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.

No abstract

Alterations of plasma metabolite profiles were studied following single or multiple oral administrations of 5-[(2-aminoacetamido) methyl]-1-[p-chloro-2-(o-chlorobenzoyl)phenyl]-N, N-dimethyl-1H-1, 2,4-triazole-3-carboxamide hydrochloride dihydrate (450191-S) in Beagle dogs. In plasma, unchanged 450191-S was not detected, but active metabolite, 8-chloro-6-(2-chlorophenyl)-2-(N, N-dimethylcarbamoyl)-4H-1,2, 4-triazolo [1, 5-a] [1, 4] benzodiazepine (M-1) appeared first, followed by four active metabolites that were hydroxylated or demethylated in the N, N-dimethylcarbamoyl side chain of M-1. At single doses of 5 to 50 mg/kg, the areas under the plasma concentration-time curves (AUCs) of the metabolites were linearly increased, showing that there was no saturable process in the steps of absorption, distribution, metabolism and excretion. After multiple administrations (50 mg/kg/d for 15 d), the same metabolites appeared in the plasma but the patterns of the plasma metabolite profiles were considerably different from those after single administrations. The peak plasma levels of M-1 and its hydroxylated metabolites in the carbamoyl side chain were attained more rapidly in the multiple administrations, demonstrating higher peak values compared to those in the single administrations, and the eliminations of these metabolites from plasma were also rapid. However, no difference in the values of the AUCs were observed between single and multiple administrations. With the other active metabolites, the peak plasma levels after multiple administrations were considerably lowered by rapid elimination, resulting in a marked increase in AUCs.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

Abstract. Tissue distribution of {Aib1, Lys17,18,19}-corticotrophin-(1-19)-nonadecapeptide amide (690024-S), iv injected to hypophysectomized rats, were surveyed by bioassay. Among the tissues examined, the largest amount of 690024-S was found in the liver during 3 h of search for the injection, while a higher concentration of the peptide per tissue weight was found in kidney. Though a small amount of 690024-S was detected in spleen, heart and lung at an early stage, it was not detectable in other tissues such as brain, stomach, small intestine, thigh muscle, fat or foetus. The peptide was found to be excreted into bile for the duration of about 2 h. It was also found that the elimination of 690024-S in blood followed biphasic first order kinetics.