Several factors affecting the bioavailability of 5, 5-diphenylhydantoin (I) and its sodium salt (I-Na) were examined in dogs in relation to meal and following results were obtained. 1) The bioavailability of I was not appreciably affected by the volume of coadmini8stered water in the range of 30-120 ml. 2) The bioavailability of I was most excellent when I was administered 0.5h after meal. Food intake 0.5h after drug administration enhanced appreciably the bioavailability, but that 2h after drug administrationn did hardly affect the bioavailability. 3) The extent of bioavailability of I-Na was almost 100% of the dose in the range of 100-400 mg/dog when it was administered 0.5h after meal. While, when I-Na was administered in the fasting state, the extent of bioavailability was about 60% of the dose. 4) Food-induced enhancement of the bioavailability of I was independent of the food constituents. 5) The bioavailability of I was increased about 1.5-fold and 2-fold with 10-fold increase in the specific surface area of I, in the nonfasting and the fasting states, respectively. 6) In the experiments using the dogs with the chronically implanted fistula in the common bile duct, it was found that the bile was not a major factor contributing to the food-induced enhancement of the bioavailability of I. 7) There was a good correlation between the bioavailability of I in dog and that in man.

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The effects of angiotensins on the motility of highly washed human sperm were examined by multiple exposure photography system. The addition of low doses (0.1-10 ng/ml) of angiotensin II (AT II) stimulated the forward velocity of sperm without increasing the percentage of motility. On the contrary, high concentration (1.0 μg/ml) of AT II suppressed the motility. The direct effect of angiotensin I (AT I) on the motility was observed under the presence of SQ 14225, a specific inhibitor of angiotensin I converting enzyme (ACE). AT I (0.1-100 ng/ml) gave no influence on the motility, whereas that of high dose (1.0 μg/ml) suppressed the motility in the same manner as the corresponding dose of AT II. The action of AT II on the motility was completely suppressed under the coexistense of saralasin, a specific antagonist anainst AT II. This fact indicated that the action of AT II on the sperm appeared through the specific receptor on sperm.

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Anti-inflammatory effects of chloride salts of praseodymium, gadolinium and ytterbium were investigated, using various experimental inflammatory models in rats. The lanthanide salts administered by oral route showed no significant effect, but when injected intraperitoneally they significantly inhibited the carrageenin-induced oedema, proportional to their doses ranging from 15 to 75 mg/kg. They also reduced nystatin- induced oedema and vascular permeability response to histamine and serotonin. Pronounced inhibitory effect of lanthanide salts at the dose of 50 mg/kg, i.p., was observed in histamine- and serotonin-induced changes invascular permeability. Repeated administration of lanthanide salts in the dose of 20 mg/kg for 13 d significantly inhibited arthritis development. The same dose of these salts for a 6-d period similarly reduced granuloma formation. However, praseodymium, gadolinium and ytterbium chlorides showed no significant difference among themselves and their anti-infammatory effects were samller than those from phenylbutazone.

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Quantitative blood levels of thyrotropin-releasinghormone (TRH) were determined a sensitive and specific radioimmunoassay after oral administration or intravenous injection of thyrotropin-releasing hormone tartrate monohydrate (TRH-T) in the rat, dog and human. A pharmacokinetic analysis after intravenous injection of the drug revealed biphasic elimination of the whole blood concentration following a two-compartment open model with a half-life in α-phase of 2.6 min and β-phase of 4.6 min in the rat (dose : 500 μg/kg); a half-life in α-phase of 3.2 min and β-phase of 18.1 min in the beagle-dog (dose : 146 μg/dog); a half-life in α-phase of 4.0 min and β-phase of 20.4 min in the human (dose : 730 μg/human). The absolute bioavailability of TRH after oral administration of TRH-T solution in 24h fasting rats were 1.5, 0.4 and 0.2% at 29.2, 146, and 730 mg/kg dosing levels, respectively (e.q. 20, 100, 500 mg/kg of TRH) compared with i.v. injection (dose : 500 μg/kg). In beagledogs, they were 12.6, 9.8, 5.6, and 2.92, 14.6, 29.2, and 146 mg/dog dosing levels, respectively (e.q. 2, 10, 20, and 100 mg/dog of TRH) compared with i.v. injection (dose : 146 μg/dog). Those of after meal in beagle-dogs were 6.0 and 2.3% at 2.92 and 29.2 mg/dog dosing levels (e.q. 2, and 20 mg/dog of TRH). Thus, TRH absorption showed apparent saturation and was decreased by food ingestion. The absolute bioavailability in the humans, who were administered 11.7 mg TRH-T (2.92 mg/tablet×four, e.q. 8 mg of TRH) two hours after meal, was 2.0% on the average, and thyroid stimulating hormone levels were significantly increased by oral administration of TRH-T tablets.

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The alterations of various enzymes responsible for drug metabolism and heme methlism were examined in regenerating lives of male rats. Microsomal cytochrome P-450 content and aminopyrine demethylase activity were significantly decreased during liver regeneration. In contrast, microsomal heme oxygenase activith was markedly increased under the identical conditions. The increased heme oxygenase activity which appeared within 4h and reached maximum at 1d after partial hepatectomy was sustained for 5d. In sham-operated rats, the changed patterns of these parameters were similar, but to a lesser extent as compared to partially hepatectomized rats. The increase of heme oxygenase activity following partial hepatectomy was blocked by the administration of cycloheximide or actinomycin D. Other enzymes involved in heme synthesis did not change appreciably during liver regeneration. The inverse relationship between the decrease of cytochrome P-450 content and the increase of heme oxygenase activity was also observed in female rats and male mice. These findings suggest that the increase of heme oxygenase activity in regenerating rodent liver would be correlated to the decrease of cytochrome P-450 content. Adrenalectomy enhanced the increase of heme oxygenase activity following partial hepatectomy, though the decrease of cytochrome P-450 was less extensive under the experimental conditions. The results also suggest that the inverse relationship between the increase of heme oxygenase activity and the decrease of cytochrome P-450 content would be a biochemical phenomenon seen in regenerating liver and that the phenomenon would not be simply due to the surgical stress to the animals.

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Nine lipophilic la-N-substituted prodrugs of mitomycin C were formulated in lipid dispersion dosage forms and their fundamental antitumor acrivities were evaluated. The prodruge were efficiently incorporated into liposome of O/W emulsion according to their increased lipophilicities, while mitomycin C was hardly entrapped into them. Almost complete incorporation was observed in nonyloxycarbonyl and cholesteryloxycarbonyl mitomycin C which showed partition coefficients over 800 in chloroform/water system. The release rate from these dosage forms determined by a dynamic dialysis method decreased with an increase in the partition coefficients of the derivatives. All prodrugs entrapped in liposome of O/W emulsion showed significant antitumor acrivities against L1210 leulemia in i.p.-i.p. system except for cholesteryloxycarbonyl mitomycin C. In spite of comsiderable antitumor activities showen in the forms of liposome and emulsion, saline suspension of nonyloxycarbonyl mitonycin C failed to exhibir any actibity because of its poor aqueous solubility. These results suggested the utility of the combining delivery system of lipophilic prodrug with physical device such as liposome and O/W emulsion.

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We investigated the reactivation of inactivated acetylcholinesterase (AChE) after 2-PAM therapy in acute fenitrothion poisonings of two species of rat and rabbit. By single treatment with 2-PAM carried out immediately after fenitrothion administration, the significant reactivations of inactivated AChE in red blood cell (RBC) and brain as well as inactivated cholinesterase (ChE) in plasma were observed at 2h after administration of 20 mg/kg fenitrothion in rat, while these reactivations became less in rats severely poisoned with 500 mg/kg fenitrothion. Although these significant reactivations disappeared 6h after the single treatment with 2-PAM, the repeated treatments with 2-PAM induced the prolongation of the reactivations of inactivated AChEs and ChE. These results suggest tnat 2-PAM would be more effective to light poisoning with fenitrothion, and that the repetition of 2-PAM treatment would be very important to obtain the sufficient antidotal actions. In rabbits as well as rats, the considerable reactivations of inactivared AChEs in RBC and brain and inactivated ChE in plasma were observed by the single treatment with 2-PAM in fenitrothion poisoning. These reactivations in brain AChE indicate that 2-PAM can penetrate the blood brain barrier of both rat and rabbit, despite its quaternary character.

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As the endothelium has an important role in the vasodilating effect of acctylcholine, we investigated the possible role of the endothelium in the vasodilating effect of platelet activating factor (PAF). Experiments were done on spirally cut rat thoracic aorta either containing or denuede of endothelial cells. It was demonstrated that relaxation by PAF and acetylcholine of pre-contracted strips required the presence of endothelial cells. The result strongly suggested the possible involvement of endothelium in the vasodilation produced by PAF as well as by ACh.

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