[The metabolic fate of o-chloro-a-(teri-butylaminomethyl)-benzyl alcohol hydrochloride (C-78). II. Metabolic products in the rat (author's transl)].
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Biomedical subjects
Publications and source records attributed to S Higuchi.
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1. After oral administration of [14C]dihydropyridine diester, the plasma concn. of radioactivity was similar in rats and dogs, reaching a maximum at 0-5 to 1 h and decreasing with a half life of about 3-5 h. The plasma concn. of unmetabolized drug in dogs was 10 times higher than in rats. Radioactivity in rat tissue was high in liver, kidney and lung after both oral and intravenous administration. 2. In both species, 66-72% of radioactivity was excreted in faeces and 23-29% in urine in 48 h, regardless of the route of administration. Biliary excretion in rats after oral dosage amounted to 65%. 3. Eight metabolites were identified from urine of dogs and rats. They were derived from one or several of the following pathways: I, debenzylation of the N-benzyl-N-methylaminoethyl side chain; II, reduction of the 3-nitro group on the phenyl substituent; III, oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine; IV, oxidative removal of the N-benzyl-N-methylamino group yielding a carboxylic acid; V, hydrolysis of the N-benzyl-N-methylamino-ethyl ester to the corresponding carboxylic acid; VI, hydroxylation of the 2-methyl group of the 1,4-dihydropyridine ring to hydroxymethyl.
When rabbit peritoneal exudate cells were incubated for 24 and 48 h with phytohemagglutinin-activated lymphocytes or their culture supernatants, two times as many cells remained adherent to culture slides as in the controls. More spreading cells were found among the adherent cells in the stimulated cultures. Eighty percent of spreading cells that were induced by supernatants were negative or faintly positive for beta-galactosidase. On the other hand, half of the spreading cells induced by activated lymphocytes were positive (1+ to 4+) for beta-lymphocytes and their supernatants. Under similar conditions, unstimulated peritoneal cells showed less marked activation. These findings show that macrophages can appear morphologically activated and yet not be enzymatically activated by lymphokines. Possible mechanisms of direct interaction of activated lymphocytes and macrophages are discussed.
A highly sensitive method for the quantitative determination of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino)]-ethyl ester 5-methyl ester hydrochloride (YC-93) in plasma is described. After extraction, YC-93 was oxidized to a pyridine analogue with nitrous acid and detected by electron capture gas chromatography. The sensitivity was 2-3 ng/ml, which is sufficient to determine plasma concentrations of YC-93 after oral administration of clinical doses to humans.
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