The pharmacokinetics of caffenine and its metabolites were studied in pregnant rats in order to clarify the effects of maternal caffeine ingestion on the caffeine disposition. On gestational day 18 the single intravenous or oral 10mg/kg dose of caffeine was administered to pregnant rats who had received drinking water containing 0.04% caffeine or water ad lib during the premation and/or pregnant periods. Concentrations of caffeine and its dimethylxanthines were simultaneously determined by high-performance liquid chromatography. The caffenine plasma concentration-time curves were analyzed by assumption of a onecompartment model. The apparent volume of distribution of caffeine in rats given caffeine only during pregnancy was decreased. The elimination rate constant (k_el) of caffeine in most of the rats taking caffeine during pregnancy was increased. The rats which had received caffeine throughout the premating and pregnant periods had a relatively high total body plasma clearance (CL) of caffeine. The k_el or CL widely varied in the rats taking caffeine during pregnancy. The individual values of k_el or CL in pregnant rats were significantly correlated with the molar concentration ratios of the metabolites to caffeine in plasma at 8 h after administration of caffeine. It is concluded that the caffeine disposition is influenced by the different modes of maternal caffeine ingestion during the premating and/or pregnant periods

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Plasma concentrations and urinary excretion of canrenone (III), canrenoic acid (IV) and canrenoic acid glucuronide (V) were determined by means of high performance liquid chromatography (HPLC) and fluorometry after oral administration of spironolactone (I) and potassium canrenoate (II) to human subjects. comparison of both assays for III in plasma as well as in urine after administration of I showed marked differences. Plasma concentrations of III were significantly higher after administration of II than I, C_max and AUC from II being 3-5 times larger than those from I by means of HPLC assay, while the fluorometrically determined values for III in plasma after administration of I and II did not differ as much from each other. On the other hand, in contrast to plasma, the amount of III excreted in urine after administration of I was much larger than that after II, i.e. 3-4 times greater by means of HPLC and over 10 times greater by means of fluorometry. These results strongly suggest that precursors of III are formed which have a higher renal clearance than that for III alone after oral administration of I. Considering the relative biological potency ratio of I and II, it is presumed that their pharmacological activities may relate to the urinary excretion of III. Plasma concentrations of IV were definitely higher after administration of II compared to those after I. Canrenoic acid (IV) was excreted mainly as glucuronide (V) in urine.

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The distribution kinetics of cefazolin in rats has been examined at four different ages (1, 7, 50 and 100 weeks). The steady state distribution volume of cefazolin, estimated from the plasma t ime course after i.v. injection of 20mg/kg, varied between 136 ml/kg (50-week-old rats) and 297 ml/kg (1-week-old rats). The extracellular fluid volume, obtained from the steady state distribution volume of inulin, varied between 126ml/kg (50-week-old rats) and 370 ml/kg (1-week-old rats). There was a good correlation between the steady state distribution volume of cefazolin and extracellular fluid volume (r=0.977). The influence of changes on the value of the plasma unbound fraction and extracellular fluid volume on the tissue-to-plasma partition coefficient of β-lactam antibiotics was simulated by using a physiological pharmacokinetic model. The results of the simulation showed that extracellular fluid volume is an important factor affecting the distribution volume of β-lactam antibiotics and that plasma binding plays a minor role on it. the experimental and simulation results suggested that the cange in the interstitial fluid volume is a determinant factor in the age-related changes in the distribution volume of β-lactam antibiotics.

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An inactive kallikrein, which could be activated with trypsin was isolated from the rat kidney cortex using diethylaminoethyl (DEAE)-cellulose chromatography. The inactive kallikrein had no vasodilator action, whereas the injection of trypsin-activated from of this enzyme into the femoral artery of dogs resulted in a marked increase in the arterial blood folw. Apparent molecular weight of the inactive kallikrein was estimated to be 4.4×10⁴ by gel filtration, and this enzyme was converted to the renal active kallikrein (M.W. 3.8×10⁴) by trypsin. the inactive kallikrein is immunologically identical with the trypsin-activated from of inactive kallikrein and active kallikrein. the were no significant differences in the chromatographic behavior on a DEAE-cellulose column, K_m value for prolyl-phenylalanyl-arginine-4-methylcoumaryl-7-amide hydrolysis and profile of inhibition by trypsin inhibitors between the active kallikrein and the trypsin-activated form of inactive kallikrein. the above properties. of the renal inactive kallikrein were similar to those of inactive kallilrein found in the urine. These results suggest that the inactive kallikrein in the rat kidney would be proteolytically converted to its active enzyme and that a part of the inactive kallikrein would be excreted into urine in a form itself.

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Effects of endotoxin on the motility, the permeability of mesentric blood vessel and endogenous substances (electrolyts (Na, K), histamine, serotonin and primary prostaglandin) in the small intestine of mice were investigated. Diarrhea was induced by intraperitoneal injection of Salmonella typhosa endotoxin in mice. It is suggested that the diarrheal action of endotoxin is due to the acceleration of intestinal motility and/or the facilitation of mesentric blood vessel permeability. On the other hand, from the observation of blood concentration of acetaminophen and sulfisoxazole, inhibition of drug absorption was suggested in cases of diarrhea induced by endotoxin. This inhibition of gastrointestinal absorption is due to the delay of the gastric emptying rate, the increase of intetinal transit time of drug in the absorption site and the acceleration of mesentric blood vessel permeability. then it is conceivable that these actions may be mediated by biogenic amines (serotonin and histamine) and primary prostaglandins.

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The product inhibition of aminopyrine (AM) N-demethylation by 4-monomethylaminoantipyrine (MAA) was examined in vitro in preparations of isolated rat hepatocytes using gas chromatograph-mass spectrometer (GC-MS). the kinetic study of AM N-demethylation, which was determined by MAA formation, was studied at concentrations from 0.2 to 4.0 mM with or without various concentrations of D₃-MAA.D₃-MAA inhibited AM N-demethylation non-competitively at concentrations of 0.2 to 1.0 mM of AM (k_i=1.81 m_M), though it did competitively at concentations of 1.0 to 4.0 mM of AM (K_i=0.81 mM). From the present observation, it was suggested that the inhibition type of AM N-demethylation by D₃-MAA was dependent on the substrate (AM) concentration.

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Effects of liver 9000×g supernatant fraction from 3, 4, 5, 3', 4'-pentachlorobipheny- and 2, 4, 5, 2', 4', 5'-hexachlorobiphenyl-pretreated rats (PenCB-S9 and HexCB-S9, respectively) on the mutagenic activities of well-known carcinogens, benzo [a] pyrene (BP), Glu-P-1 (2-amino-6-methyldipyrido [1, 2-a : 3', 2'-d] imidazole), Trp-P-1(3-amino-1, 4-dimethyl-5H-pyrido [4, 3-b] indole), and aflatoxin B₁ (AFB), toward Salmonella typhimurium TA 98 have been described. Although the mutagenic activities of all of these carcinogens were enhanced by these S9, PenCB-S9 sepecially highly activated BP, Glu-P-1, and Trp-P-1. The ability of PenCB--S9 to activate the carcinogens was much higher than that of liver 9000×g supernatant fraction from 3-methylcholanthrene-pretreated rats (MC-S9). PenCB-S9 enhanced the mutagenic activity of BP 8 times higher than MC-S9, while Glu-P-1 and Trp-P-1 were activated by PenCB-S9 twice as much as by MC-S9. Effect of HexCB--S9 on the mutagenic activities of the above-mentioned three carcinogens was much less than those of PenCB- and MC-S9 and a little higher than that of 9000×g supernatant fraction from rats pretreated with phenobarbital. As for AFB, phenobarbital was the most potent inducer, and HexCB and PenCB were next to this. Data suggest that PenCBis a strong inducer of P-448 species which activate environmental toxicants.

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Disappearance from the blood and lymphatic delivery of human fibroblast interferon (HuIFN-β) in rats by the various administration routes were studied. Intravenous injection showed a rapid disappearance of HuIFN-β from the blood circulation, however, the clearance rate was greatly decreased after 2 h and the half-lives were 15 min and 2.0 h. Intramuscular, subcutaneous and intraperitoneal injections maintained readily detectable levels in the blood for 12 h, and the half-lives were 2.3, 1.7 and 1.2 h, respectively. Lipid-surfactant mixed micelles greatly promoted the absorption of HuIFN-β from the large intestine with extremely high selective lymphatic delivery, whereas intravenous and intramuscular injections showed no selective transfer into the lymphatics.

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The promoting mechanism by bile salts in rat recatal absorption of antipyrine was studied by the in situ recirculating perfusion. The significant correlation between rectal absorption clearance (CL_AP) of antipyrine (AP) and apparent water influx (infulx') was found in the control without promoters, indicating the existence of solvent drag in the AP rectal absorption. Sieving coefficient of AP (b_AP), i.e. the slope of the regression line between CL_AP and influx', was 0.6 approximately equal to that in small intestine reported previously. The relation between the promoting effects and solvent drag was further studied, resulting that both CL_AP and influx'were significantly enhanced by sodium taurocholate (TC-Na), sodium glycocholate (GC-Na) and sodium cholate (C-Na). Accordingly the promoting effects of bile salts might be due to the increase in solvent drag. However TC-Na did not produce the significant change in b_AP. From these results, the enhancing mechanism in the epithelial cell membrane transport was discussed.

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The biological and immunomodulating activities of polysaccharide fraction (GF-1), an antitumor poysaccharide fraction from cultured fruiting bodies of Grifola frondosa, was examined in mic. GF-1 showed no cytocidal effect on culturing tumor cells. However, GF-1 induced resistance against Sarcoma 180 in ICR mice which had completely regressed from the tumor by the effect of GF-1. The administration fo GF-1 into mice increased the weights or cell numbers of spleen, and peritoneal cavity. GF-1 enhanced the antigen specific antibody response and carbon cleatrance activity, whereas GF-1 did not show polyclonal B cell activation and mitogenic activities, and the effect on delayed type hypersensitivity.

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A radioimmunoassay of bencyclane in human serum was developed. Male rabbits were immunized with p-(3-carvboxy-propoxy) bencyclane-bovine serum albumin conjugate, giving antisera with high titers. ¹²⁵I-p-Hydroxybencyclane with a high specific activity was prepared as a labelled antigen by a chloramine-T method. In the radioimmunoassay procedure, a mixture of serum sample, diluted antiserum and ¹²⁵I-antigen solution were incubated at 4°C for 18 h, and bound-free separation was carried out by a dextran-coated charcoal method. The detection limit of bencyclane in human serum was 1.0 ng/ml, and the crossreactivity of the antiserum with metabolites was found to be wery low. Serum samples from healthy volunteers dosed orally with bencyclane fumarate were analyzed by both of the radioimmunoassay and gas chromatography-mass spectrometric methods. An excellent correlation was observed between the values obtained by both methods.

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