Pharmacokinetic analysis on glucose tolerance curves in genetically diabetic KK-CA^y mice treated with hypoglycemics was investigated using an analog computer. The glucose tolerance curves in KK-CA^y mice showed humping phenomena. They could not be simulated by a simple compartmental model, but might be fitted to the model containing the non-linear function."Compartment-H" model was contrived by adding the H-factor between glucose and insulin compartments. All the glucose tolerance curves in the KK-CA^y mice could be simulated reasonably by this model and some suggestions on the humping effect were obtained from the analysis of H-factor. The H-factor was observed to be influenced by adrenergic α-blocker. This pharmacokinetic approach was indicated to be useful for the pharmacological research.

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The inhibitory effect of bumetanide on the accumulation of p-aminohippurate (PAH) in rat kidney slices was investigated. Bumetanide increased the K_m value for PAH while the V_max remained to be constant, indicating a competitive inhibition of PAH uptake by bumetanide in the slices. Addition of bumetanide to the medium increased the efflux of PAH with which the slices were preloaded. These data suggest that the inhibitory effect of bumetanide on PAH accumulation is due to an decrease in the PAH transport to the slices from the medium as well as an increase in the efflux of PAH. The present study suggests that the effect of bumetanide was not mediated by the changes of the intracellular contents of electrolytes, Na⁺, K⁺, Ca²⁺ and Mg²⁺.

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A new radioimmunoassay, using ³H-cyclazocine, rabbit antiserum and charcoaldexttan separation of bound and free cyclazocine, for the direct analysis of serum cyclazocine is described. This method, which is specific for cyclazocine and has a detection limit of ca. 25 pg/assay tube, was successful in determining the cyclazocine level in the sera of beagles intramuscularly injected with 3 or 10μg/kg cyclazocine. The drug half-life was 90 min ; the apparent distribution volumes were 4.0 and 5.26 liter/kg, respectively. One of the antisera raised in rabbits immunized with dl-cyclazocine derivative-BSA conjugates was highly specific for l-cyclazocine.

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There are potent kinin degrading activities in seminal plasma and testis of various mammals. The activities in boar and human seminal plasma, and testis extracts from boar, rat, guinea pig and rabbit were eluted out at a similar position as a single peak in column chromatography with Sephadex G-200 or DEAE Sephadex A-50. These enzymes degraded synthetic bradykinin and yielded angiotensin II from angiotesin I by cleaving the second peptide bond from the carboxytermini of the substrate, and it was concluded that these enzymes were dipeptidyl carboxypeptidases like kininase II or angiotensin I converting enzyme. The enzymes in male genital organs of these mammals were found to be identical with further investigation on the enzymic properties of them. The enzyme in rat testis increased significantly in accordance with sexual maturation, and the increase was suppressed by injection of danazol or diethylstilbesterol to rats. Furthermore, the dipeptidyl carboxypeptidase content in human seminal plasma was positively correlated to the semen qualities, i. e. sperm density and motility. From these results it is supposed that dipeptidyl carboxypeptidase in male genital organ and its secretion seem to be related to the male reproductive functions.

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The present study was performed to investigate the enzymatic changes in dystrophic chickens compared to those of dystrophic mice. The activities of 14 kinds of aminopeptidases, 5 kinds of endopeptidase, 4 kinds of glycosidases, phosphatase, esterase, and ribonuclease were measured in muscles of control and dystrophic chickens. When the enzyme activities were expressed as specific activity per unit weight of organs, only some of them were found to be significantly elevated in dystrophic chickens ; e.g., alanine aminopeptidase (Ala-AP), Gly-AP and cathepsin D. On the contrary, the activities of α-D-glycosidase, α-D-galactosidase and α-D-mannosidase were significantly decreased. Muscular protein contents of dystrophic chickens also tended to be lower than those of controls. These observations offer a striking contrast with the one obtained in the study on dystrophic mice. However, when expressed as specific activity per mg protein, many enzyme activities were found to be significantly elevated suggesting an extensive abnormality of metabolism in dystrophic chickens. Among 14 kinds of aminopeptidase activities, highly significant elevations were seen especially in AP-A, AP-B, Gly-AP, Ala-AP, Ser-AP, Pro-AP, Leu-AP, Met-AP and Trp-AP. Interestingly enough, a statistical approach suggested a significant correlation between the aminopeptidase changes of dystrophic chickens with those of dystrophic mice. In addition to aminopeptidases, there were highly significant increases in the activities of cathepsin D, α-D-glucosidase, β-D-galactosidase, α-D-mannosidase, esterase and RNase. These results indicate that the intramuscular metabolic abnormality of dystrophic chickens are generally different from but partly resembled with those of dystrophic mice.

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Mercury distribution and placental transfer in mice were investigated with coadministration of selenite. Pregnant mice, subcutaneously injected with 1.5 or 15.0 μmol/kg of mercuric chloride and 0, 1.3, 12.7 or 25.3 μmol/kg of sodium selenite on day 16 of their gestation, were examined for tissue distribution of mercury 24 hours after treatment. Elevated mercury concentrations in the blood were found along with increasing doses of selenite at the two dose-levels of mercury, on the other hand, decreased accumulation of mercury with increased doses of selenite was found in the kidneys and brain. In the liver, the largest amount of mercury was accumulated by approximate-equimolar combinations of doses. The amount of mercury transferred to the fetus was remarkably reduced in the groups injected with 12.7 μmol/kg of selenite at the two dose-levels of mercury. In the groups injected with higher dose of mercury, where fetal organs were measurable for mercury, fetal brain, liver or kidneys of the group of selenite 12.7 μmol/kg contained the least amount of mercury among the groups. All of the mice injected with 15.0 μmol/kg of mercury and 25.3 μmol/kg of selenite aborted before sacrifice.

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Piperidine levels in the brain and adrenal gland of rats during development were determined by mass fragmentography with deuterium-labeled piperidine as an internal standard. The levels in both organs showed distinct developmental changes, and two peaks were observed in association with the development of each organ. The initial peaks appeared in the early stage of development, that is, at the 19th day of gestation for the brain and 1 week after birth for the adrenal gland. The second peaks appeared at the age of sexual maturation (10 weeks after birth). The significance of the finding is discussed with respect to a presumed role of piperidine as a neuroendocrine modulator.

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Antitumor activity of seven 5-fluorouracil derivatives having carbamoyl linkage with amino acid was examined against L-1210 leukemia, adenocarcinoma 755, ascites sarcoma 180, Ehrlich ascites carcinoma and Lewis lung carcinoma by oral administration. These compounds showed more than 30% increase in life-span (ILS) against L-1210 at optimal doses when given by oral administration. Therapeutic ratios (ILS_max/ILS₃₀) of 1-methoxycarbonylmethylcarbamoyl and 1-(1-ethoxycarbonyl-3-methylthiopropylcarbamoyl) derivatives of 5-fluorouracil in L-1210 system were 4.8 and 4.7, respectively. 1-Methoxycarbonylmethylcarbamoyl and 1-(2-ethoxycarbonylethylcarbamoyl) derivatives of 5-fluorouracil inhibited completely the growth of adenocarcinoma 755 when given orally, but only 1-methoxycarbonylmethylcarbamoyl derivative inhibited 99 and 98% of the growth of ascites sarcoma 180 and Ehrlich ascites carcinoma, respectively. The latter compound increased the life-span to 48% at optimal dose in Lewis lung carcinoma system.

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Prednisolone was detected in the brain of rat fetus subcutaneously administered prednisolone 17-acetate. After the subcutaneous injection of betamethasone 17-propionate or dexamethasone 17-propionate to rat fetus, the unchanged steroid was detected mainly in the brain. The hydrolytic rates of prednisolone 17-acetate, betamethasone 17-esters (acetate, propionate) and dexamethasone 17-esters (acetate, propionate, valerate) in the livers of rat fetuses were studied. Prednisolone 17-acetate was hydrolyzed to prednisolone very rapidly. Betamethasone 17-esters and dexamethasone 17-esters were hydrolyzed more slowly. The hydrolytic rate of dexamethasone acetate among the dexamethasone 17-esters was the most rapid, followed by propionate and valerate. The adrenals of rat fetuses became significantly atrophied after subcutaneous administration of dexamethasone and its 17-esters. The simultaneous administration of betamethasone 17, 21-dipropionate and its metabolite betamethasone impaired the hypertrophic effect of the former on the adrenal weights of rat fetuses. The effects of the hydrolytic rate of these glucocorticoid 17-esters and of C16-methyl conformation on the hypothalamo-pituitary-adrenal system in rat fetuses are discussed.

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Radioimmunoassays have been developed which enable accurate and sensitive determination of gliclazide in human serum. Antisera A and B against gliclazide were obtained from guinea pigs immunized with conjugates A and B prepared by coupling gliclazide homologues, 1-(p-toluenesulfonyl)-3-(4'-carboxypiperidino) urea and 1-(4-methyl-3-carboxybenzenesulfonyl)-3-(3-azabicyclo [3, 3, 0] oct-3-yl) urea, to bovine serum albumin. ³H-Gliclazide was used as a tracer. Dextran-coated charcoal was used to separate bound and free ³H-gliclazide in the reaction mixture. The assays of gliclazide in serum were possible over a concentration range from 0.25 to 20 μg/ml with the antiserum A and from 0.1 to 10 μg/ml with the antiserum B, respectively, using 0.01ml of human serum without the need for an extraction procedure. The antisera used for the assays were specific for gliclazide. Data obtained by the radioimmunoassay with the antiserum A are in good agreement with those by the radioimmunoassay with the antiserum B and gas-liquid chromatography. Serum levels of gliclazide in healthy volunteers receiving single oral dosing (40 mg/subject) have also been determined.

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Dopamine relaxed catch contraction of an isolated molluscan smooth muscle (anterior byssus muscle of Mytilus edulis). A dose response curve of dopamine was shifted in a parallel fashion by a dopamine antagonist, domperidone, suggesting a competitive antagonism. Alpha-and beta-adrenoceptor blockers did not influence the response to dopamine. The potency order of dopamine antagonists used in this muscle was similat to that in the mammalian tissues.

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Oral administration of acetylsalicylic acid (ASA) at a dose of 200 mg/kg produced a decrease in both total plasma calcium and plasma ionic calcium levels in rats. The percent changes from controls in both total and ionic calcium were similar, being approximately 13% at 3 hr after the administration. A significant (p<0.01) decrease in plasma calcium level was also observed at 4 hr after oral administration of salicylic acid at a dose level of 177 mg/kg. However, oral administration of other non-steroidal anti-inflammatory agents such as indomethacin failed to decrease plasma calcium levels in rats. The hypocalcemic effect of ASA was recognized in parathyroidectomized rats, but neither in thyroparathyroidectomized nor in thyroidectomized rats. Therefore, the data suggested that the action of ASA might be mediated by stimulation of calcitonin release, but not by inhibition of prostaglandin biosynthesis.

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The enhancement of aspirin and o-ethoxybenzoic acid (but not salicylamide) absorption by taurine was cancelled by the complete replacement of NaCl with mannitol or by the presence of ouabain in the NaCl medium. It seems to require Na⁺. Homotaurine showed a similar mode of action, while the effect of glycine, the other absorption promoter, on both aspirin and salicylamide absorption was independent of the presence of Na⁺. The mechanism of action of these amino acid-like absorption promoters is speculated to be not uniform.

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