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Biomedical subjects

K Nambu

Publications and source records attributed to K Nambu.

34 records · Page 2Linked to original sources
PubMed1979

Disposition and metabolism of [14C]loperamide in rats.

Following oral administration of [14C]loperamide hydrochloride in 1 mg/kg to rats, plasma levels of radioactivity reached maximum at 4 hrs and decreased with a half-life of 4.1 hrs. Radioactivity in 96-hr feces accounted for 95% of the dose, with 30% associated with unchanged drug, while that in urine only 3.5%. Radioactivity in 48-hr bile accounted for 42% of the dose associated entirely with metabolites. 3% of the dose was found at the level of the enterohepatic cycles. These findings show that about 70% of the dose with absorbed by intestine, the target tissue of the drug, a portion (30%) of which was excreted back into intestinal cavity after demethylation, while the remaining 40% transferred to liver by which it was extracted mostly, metabolized extensively and excreted largely into bile, as supported by in vitro demethylating activity in gut segments but none in gut contents, and by in situ marked hepatic extraction of the drug. Main metabolic pathways involved are described.

Animals↗
PubMed1975

Utilization of adenosine for nucleotide synthesis in the erythrocytes of some animals.

Erythrocytes of human, monkey, dog, rat, mouse, guinea pig, hen, or frog were incubated with [U-14C]adenosine at a concentration of 0.23 muM, a level roughly corresponding to its plasma level in mammals. Direct utilization of adenosine by phosphorylation (the kinase pathway) and indirect utilization via hypoxanthine (the hypoxanthine pathway) were analyzed from the ratio of the specific radioactivities of nucleotide and base, as described previously (1,2). Both human and monkey cells efficiently utilized adenosine only by the kinase pathway, while rodent cells used the same route with an efficiency which varied with the species. Canine cells incorporated adenosine in extremely small amounts both by the kinase pathway and via the hypoxanthine pathway with a marked predominance of the former. Frog erythrocytes were similar to dog cells in mechanism of utilization, but the efficiency was of the same level as that of the primates. In contrast to other animals tested, the avian cells utilized twice as much adenosine via the hypoxanthine pathway as by the kinase pathway.

Adenosine↗
PubMedDate not supplied

Autoradiographic and biochemical studies of drug distribution in the liver. I. [14C]Dehydrocorydaline.

Whole body autoradiography revealed that the distribution pattern of [14C]dehydrocorydaline in the mouse and rat liver was heterogeneous (or reticular) regardless of time after intravenous administration of the labeled agent. Microautoradiography by dry-mounting method revealed that the macroscopic heterogeneous pattern was due to the periportal localization of the radioactive compound in the hepatic lobule. By comparison with [14C]salicylid acid, [14C]diphenylhydantoin and [14C]p-chlorophenoxyacetic acid whose distribution pattern are homogeneous in the liver, the present studies indicated that the existence and persistence of heterogeneous distribution of [14C]dehydrocorydaline in the liver had the following causes: 1. Shortly after intravenous administration, the amount of [14C]dehydrocorydaline circulated to the liver was greatly restricted by its significant distribution in non-hepatic tissues. This was shown by the whole body autoradiography, radiometry of tissues and quantitative comparison of volumes of distribution in non-hepatic tissues. Therefore, 2. perilobular hepatocytes alone could take up [14C]dehydrocorydaline and consequently, centrilobular cells were unavailable to it: heterogeneous distribution pattern is formed. This was shown by microautoradiography as described above, and by the rapid and significant uptake of [14C]dehydrocorydaline by isolated hepatocytes in vitro and by the liver to which the labeled agents were continuously administered in situ. It was also substantiated by the more homogeneous distribution pattern in the liver of the rat to which greater amount of [14C]dehydrocorydaline was gradually given into the portal vein and of the mouse with allyl formate-induced perilobular damage. 3. Redistribution of [14C]dehydrocorydaline scarcely occurred in the whole body and therefore radioactive substance was not significantly supplied to the liver: the distribution pattern remained unchanged. This was shown by the whole body autoradiography and radiometry of tissues.

Alkaloids↗
PubMedDate not supplied

Autoradiographic and biochemical studies of drug distribution in the liver. II. [35S]Chlorpromazine and [14C]imipramine.

Whole body autoradiography revealed that the distribution pattern of [35S]chlorpromazine and [14C]imipramine in the mouse and rat liver was heterogeneous (or reticular) shortly after intravenous administration of the labeled agents and then became homogeneous. Microautoradiography by dry-mounting method revealed that the macroscopic heterogeneous pattern of [35S]chlorpromazine was due to its periportal localization in the hepatic lobule. The present studies indicated that the heterogeneous distribution was re-arranged to a homogeneous one in the following way: 1. The amount of [35S]chlorpromazine and [14C]imipramine circulated to the liver was greatly restricted by their significant distribution in non-hepatic tissues shortly after administration. This was shown by whole body autoradiography, radiometry of tissues and volumes of distribution in non-hepatic tissues. Therefore, 2. perilobular hepatocytes alone could take up the agents and consequently, centrilobular cells were unavailable to them: heterogeneous distribution pattern is formed. This was shown by microautoradiography described above, and by the rapid and significant uptake of the agents by isolated hepatocytes in vitro and of [35S]chlorpromazine by the liver to which the agent was continuously administered in situ. However, 3. re-distribution of [35S]chlorpromazine and [14C]imipramine occurred thereafter. Therefore, the radioactive compounds were significantly supplied to the liver late after administration: the pattern became homogeneous. This was shown by the whole body autoradiography and radiometry.

Animals↗
PubMedDate not supplied

Absorption of intramuscularly administered [14C]haloperidol decanoate in rats.

When [14C]haloperidol decanoate, an ester of haloperidol and decanoic acid, was given intramuscularly to rats, levels of total radioactivity and haloperidol decanoate in medial iliac and hypogastric sacral lymph nodes nearest to injection sites were the highest in examined lymph nodes and plasma. These lymph node levels became maximum 16 days after administration and declined gradually with half-life (around 14 days) similar to those of plasma total radioactivity, haloperidol decanoate and haloperidol. However, when the labelled ester was given intravenously, plasma total radioactivity disappeared far more rapidly. Much more radioactivity was found in hind limbs whose femoral muscles had been injected than in other body parts, even at late stages after administration. Haloperidol alone was found in the brain after [14C]haloperidol decanoate was given either intramuscularly or intravenously. It was concluded that haloperidol decanoate injected in rat femoral muscle was rate-limitedly distributed in lymph circulation and that the absorbed ester did not penetrate the brain through the blood-brain barrier but formed haloperidol did.

Absorption↗
PubMedDate not supplied

Hydrolysis of haloperidol decanoate in vitro by cultured cells.

[14C]Haloperidol decanoate was hydrolysed by partially purified carboxylesterase but not in plasma, blood, lymph and lymphatic liquid. These fluids inhibited the enzyme-mediated hydrolysis of the ester. Within the same incubation period as above, the ester was found hydrolysed to various extents in cell cultures of isolated rat liver cells, of human and rat lymphocytes and of established cell lines (BGM cells, WI-38 cells and L6 cells). Thus, the hydrolysis of the ester was demonstrated in vitro with use of viable cell cultures instead of enzyme preparation. From the time course study on the metabolism of haloperidol decanoate in cell cultures, it was concluded that haloperidol decanoate was first concentrated in the cells and hydrolysed to haloperidol. Based on these results, the metabolic sequences in vivo leading to the formation of active principle haloperidol after intramuscular administration of its decanoate were discussed.

Animals↗
PubMedDate not supplied

Studies on disposition and metabolism of tolmetin, a new anti-inflammatory agent, in rats and mice. I. Absorption, distribution, and excrection of [14C]tolmetin radioactivity.

[14C]Tolmetin was rapidly and almost completely absorbed in both rats and mice. The major portion of the drug was shown to be absorbed from the upper part of the duodenum, and a small portion from the stomach. Tissue levels of radioactivity comparable to blood levels were found only in liver and kidney, and other tissue levels were lower than those in blood, possibly because of the considerable plasma protein binding of the drug. Radioactivity disappeared from most tissues at rates similar to that from blood, and no appreciable radioactivity was found in rat and mouse tissues 24 hr after dosing. Correspondingly, radioactivity was excreted mostly in urine within this time period. Mouse fetuses contained significantly less radioactivity than did maternal tissues in autoradiography. No significant differences were found in absorption, distribution, and excretion of radioactivity when single or five consecutive daily doses of [14C]tolmetin were administered to rats.

Animals↗
PubMedDate not supplied

Studies on disposition and metabolism of tolmetin, a new anti-inflammatory agent, in rats and mice. II. Urinary metabolites.

A new urinary metabolite of tolmetin was found in rat urine and identified as the hydroxymethyl metabolite (tolmetin-OH), an intermediate in the formation of the known carboxy metabolite (tolmetin-COOH). In rats of two strains, the following percentages of the urinary reactivity of [14Ia1tolmetin were found in 24 hr: unchanged tolmetin-COOH (58--60%), tolmetin-OH (18--24 %), and its conjugate 6--14%. Mouse urine contained the unchanged drug (about 20%), its conjugate and tolmetin-COOH (60%). Similarly to mouse urine, human urine contained negligible amounts of tolmetin-OH.

Animals↗