From the view points of safety and efficacy of sodium guaiazulene-3-sulfonate (GAS) after oral cavity administration, the absorption behavior of GAS was investigated in rats and rabbits and following results were obtained. 1) GAS was absorbed not from oral cavity but from nasal cavity in rats and rabbits. 2) The in situ perfusion experiments revealed the existence of dose-dependent specific absorption mechanism in the rat small intestine. 3) GAS was absorbed from neither the rat stomach nor the rectum. These facts reveal that GAS transfers into the systemic circulation only through the small intestine after the clinical application to the oral cavity. And these absorption characteristics of GAS are suited for its direct action on the inflamed oral mucosa. When GAS is administered into the oral cavity, the safety is at least the same as that obtained after oral administration.

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To examine the absorption mechanism of sodium guaiazulene-3-sulfonate (GAS) through the nasal and the intestinal membrane, the apparent absorption rate under the various experimental conditions was measured with the in situ perfusion method in rats, and the apparent partition coefficient of GAS was also determined. The absorption rate of GAS changed biphasically depending on the initial GAS concentration in the perfusate. At the lower concentration range (<1 mg/ml), the absorption rate of GAS decreased with the increased in the concentration, and the absorption was inhibited by HgCl₂ and ouabain. However, at the higher concentration range (>1 mg/ml), the absorption rate from the nasal mucosa increased markedly with the increase in the concentration, and ouabain had no effect. The apparent partition coefficient of GAS increased with the increase in the concentration of GAS, and GAS was found to be readily transferred to the organic phase by forming ion-pair complexes with the cation such as NH₄⁺ion. These results suggested that GAS is absorbed through the nasal membrane by at least two kinds of mechanisms : one is a carrier mediated system and the other is a hydrophobic interaction with the nasal mucosa which is increased by forming an ion-pair complex of GAS with cation.

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Effect of an N-succinyl-L-trialanine p-nitroanilide-hydrolyzing protease (STA-protease) purified from Pronase on glucose metabolism was investigated by an intravenous injection into fasted mice. The maximum decrease in blood sugar level by STA-protease was observed 2 h after the injection of a dose of 5.0 mg/kg. The hypoglycemic activity was observed with other microbial proteases, such as Pronase E and subtilisin BPN', whereas no activity was found with the modified enzymes which almost wholly lost their proteolytic activities by the treatment with diisopropyl fluorophosphate or guanidine HCl. The increase in blood sugar level by epinephrine and the conversion of [1-¹⁴C] pyruvate into blood glucose were distinctly suppressed with STA-protease as well as 5-methoxyindole-2-carboxylic acid (MICA), an inhibitor of gluconeogenesis. A slight increase in glycogen content in diaphragm of mice was observed during 2-4 h after the injection of STA-protease, though it was markedly increased by insulin. In test of glucose tolerance, the increase in blood sugar was distinctly suppressed by insulin but not by STA-protease. Blood lactate level was not subjected to change by STA-protease, in contrast to MICA. Serum insulin level was not affected by STA-protease. Therefore, STA-protease may affect the in vivo metabolism of glucose in a different way from the in vitro action which has been reported to react with cell surface and consequently to mimic the actions of insulin.

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To examine the bioavailability of nitroglycerin in sublingual tablet, 5 healthy adult volunteers underwent simultaneous sublingual administration of a table prepared with methylcellulose and a tablet prepared with lactose containing 0.15 mg of nitroglycerin and 0.15 mg of nitroglycerin-¹⁵N₃, respectively. In 4 of 5 volunteers, no difference in plasma concentration determined by gas chromatography-mass spectrometry (GC-MS) was observed between 2 tablets described above, so it was well accepted that nitroglycerin in tablets prepared with methylcellulose had a similar bioavailability to that in tablets prepared with lactose. The simultaneous administration of the 2 nitroglycerin tablets to a healthy volunteer, one of which containing the drug labeled with a stable isotope followed by GC-MS assay, seems to be the most suitable method for a precise comparison of bioavailability of the formulations.

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Urinary excretion characteristics of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), following intravenous administration was studied in rats. Three types of MMC-D, conjugates with dextrans of molecular weights of 10000, 70000 and 500000, were tested and urine concentration of MMC, dextran and spacer were determined by three analytical methods, i.e., bioassay, anthrone method and radioactivity counting. MMC was assayed separately as a free form and conjugated form based on antimicrobiological activity. MMC administered as a free form was excreted rapidly into urine but only a small amount of MMC was excreted following the administration of MMC-D. The excreted amount of MMC in a conjugated form varied with the size of carrier dextran while similar sustained excretion was observed regardless of the carrier size. The excretion of carrier dextran determined by anthrone method was confined as the molecular weight was increased. The effect of molecular weight was also observed in the case of spacer-introduced dextran (dextran-C₆ spacer) and original dextran. Compared with neutral dextran, cationic MMC-D and anionic dextran-C₆ spacer exhibited diminished excretion, indicating the effect of charge on urinary excretion. The urinary recovery of radioactivity was almost in accordance with that of carrier dextran. However, the urinary recovery of MMC based on biological activity was considerably lower than that of carrier dextran. It was suggested that MMC-D underwent inactivation to a great extent before releasing active MMC in the body. The effect of physicochemical properties such as molecular weight and electric charge on the urinary excretion of the polymeric prodrug was thus elucidated.

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Pharmacokinetic relationships have been developed to characterize a one-compartment drug disposition model which includes perfusion limited elimination processes. The derived expressions have been applied to plasma concentration and urinary excretion data obtained after rapid intravenous administration of 4-aminoantipyrine to rabbits. The mathematical relationships and experimental data demonstrate that dose dependent disposition of 4-aminoantipyrine is a result of reduced renal and hepatic blood flow caused by the drug itself.

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The effect of acute renal failure (ARF) on the disposition of phenolsulfonphthalein (PSP) after intravenous administration was investigated in rats. ARF was induced by the subcutaneous injection of uranyl nitrate to rats. Renal excretion of PSP decreased significantly in ARF compared to that in normal controls. On the other hand, rats with ARF showed an increased biliary excretion of PSP to compensate for reduced renal excretion of the drug. Consequently no significant change was found in total body clearance of PSP between control and ARF. The in vitro binding experiment showed that the binding fraction of PSP to ARF plasma was significantly lower than that to control plasma. In order to clarify the regulatory mechanisms of PSP excretion between liver and kidney in ARF, we developed a simultaneous perfusion system of rat liver and kidney, which could control the flow rate and the constituent of the perfusate. In this perfusion system, neither biliary excretion nor the protein binding of PSP differed significantly between control and ARF, though its renal excretion decreased in ARF in a similar manner as in vivo. These results suggest that alterations in plasma protein binding as well as renal excretory function are determinants of PSP disposition in ARF.

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Therapeutic dose (20, 40 and 80 μg/man) of clenbuterol hydrochloride, a β₂-adrenergic stimulant, was orally administered to healthy volunteers, and the unmetabolized drug in plasma and urine was determined by enzyme immunoassay. The plasma levels of clenbuterol reached the maximum value of 0.1, 0.2 and 0.35 ng/ml, respectively, in a dose-dependent manner within 2.5h, which lasted for over 6 h after the administration. The half-life of clenbuterol in plasma was estimated to be about 35 h. When the drug was orally administered repeatedly to men twice a day, the plasma level reached the plateau within 4 d after the initial administration. At that time, the plasma levels of the unchanged form were 0.2 to 0.3 ng/ml and 0.5 to 0.6 ng/ml at doses of 20 and 40 μg/man, respectively. The bound ratio of the drug to plasma protein was estimated to be 89-98% at a single administration of 80 μg of the drug. The cumulative urinary excretion of unchanged compound corresponded to about 20% of the administered dose as measured at 72 h following a single oral administration. When clenbuterol hydrochloride was orally administered to rats at a dose of 2μg/kg, the plasma level reached the maximum at about 1 h after the administration. In rabbits, the plasma concentrations reached the maximum value of about 0.2 and 0.8 ng/ml within 2 h following administration of clenbuterol hydrochloride at doses of 0.5 and 2 μg/kg, respectively. The half-life of clenbuterol in plasma was about 30 h in rats and about 9 h in rabbits.

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