Diethylethoxymethylene malonate (DEEMM) and diethyl maleate (DEM) enhanced the rectal absorption of cefmetazole in rats when studies were carried out using in vivo, in situ rectal loop and in vitro rectal everted sac method. Since an increase of cefmetazole transport was found when concentration of nonprotein sulfhydryls in rectal tissue was decreased by the presence of either DEEMM or DEM in the study using in vitro everted sac method and the enhancement of cefmetazole absorption by the coadministration of either DEEMM or DEM was suppressed by the treatment with dimercaprol, membrane permeability of rectal tissue seems to be regulated by the concentration of nonprotein sulfhydryls in rectal tissue. On the other hand, it was also found that there were differences between the action of DEEMM and the action of DEM from the following two results : 1) enhancing action of DEEMM was suppressed by the presence of calcium ion in microenema while action of DEM was not so much influenced, and 2) DEEMM enhanced the rectal absorption of lysozyme in rabbits but DEM did not.

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A lectin was isolated from the external mucous of fish, Genypterus blacodes. This is the first lectin isolated from fish. The molecular weight of the lectin, determined by gel filtration, was approximately 32000, whereas 8000 was indicated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence of 2-mercaptoethanol. Amino acid analysis demonstrated that the lectin contained large amounts (near 30% of the residues) of lysine, but no tryptophan. The lectin agglutinated mouse, rabbit and human erythrocytes at a concentration of 15.6μg/ml. An inhibition test revealed that the lectin was strongly inhibited by N-acetyl-glucosamine, mucin and orosomucoid. Binding studies performed with iodinated asialo-orosomucoid indicated that the lectin contained a high affinity binding site with a dissociation constant of 1.1×10^-8M. The lectin required the presence of calcium ion for both its hemagglutination and binding activity.

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The regional distribution of the conjugation reaction activities of harmol was examined in isolated rat liver cells fractionated to the centrilobular and periportal regions. The heterogeneous distribution in the conjugation rates per unit cell numbers was found only in glucuronidation. The difference in the metabolic intrinsic clearance per total cell numbers in each region was mainly due to the cell numbers, resulting that the metabolic abilities in both reactions are higher in the periportal region than the centrilobular region. This finding in sulfate conjugation is consistent with the results in the isolated perfused liver previously presented by other investigators but the result that in glucuronide conjugation is contradictory to them.

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Bioavailability after giving oral doses of 62.5mg griseofulvin tablets having different dissolution rates to stomach-emptying controlled rabbits, was estimated and compared with that in humans receiving 125mg dose of the same griseofulvin preparations. The relative differences in C_max and AUC_∞ between the product with the highest availability and others tended to be greater in rabbits than in humans. The in vivo parameters correlated well between the two species. However, power analysis indicated a larger variability of C_max in rabbits than in other species (dogs, minipigs and humans). Water volume (5 and 50ml) coadministered with the drug did not significantly influence the bioavailability. The rabbits which were not given food after oral dosing with griseofulvin exhibited a lower C_max than those which were fed immediately after dosing. The bioavailability of an ultramicronized formulation in rabbits was higher after the postprandial dose than after the preprandial dose. Food intake just after the drug administration seems to be an important factor for controlling the passage rate of the drug through the gastrointestinal tract in stomach-emptying controlled rabbits.

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Estradiol benzoate (EB), testosterone propionate (TP), progesterone (PG), corticosterone (CS), 3-methylcholanthrene (MC) and phenobarbital (PB) were administered to Wistar rats and their effects on hepatic sulfotransferase (ST) activities toward androsterone (AD) and 4-nitrophenol (NP) were determined. ST activity toward AD was increased by pretreatment with EB and PG in male rats. ST activity toward NP was increased by administration of TP and PG in females, whereas the enzyme activity was suppressed by pretreatment with EB in males. Administration of CS, MC and PB did not significantly affect ST activities toward AD and NP. These results indicate that sex difference in rat liver ST activities appears to be primarily regulated by androgenic, estrogenic and progestational hormones.

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We have investigated the promotive effect of various agents on percutaneous absorption of 6-carboxyfluorescein (CF), a water-soluble fluorescent dye, as poorly absorbable drugs. The absorption of CF was determined by measuring rat plasma CF levels. As an absorption promoter, several reagents such as surface-active agents, protein solubilizers and permeation promoters were used. The used concentration of the reagents was determined so as not to make a trauma on the skin. As results, plasma CF levels following the co-administration of 0.05 w/v% sodium dodecyl sulfate and 0.1 v/v% 2-mercaptoethanol showed the highest values. Plasma CF level was increased 40 times as compared to that of control experiment and was increased 9 times as compared to that of pretreatment with 4 w/v% calcium thioglycolate which was reported previously as a strong absorption promoter for theophylline by us. When the stratum corneum, having a barrier function for percutaneous absorption of many compounds, was removed mechanically, plasma CF levels of control experiment and pretreatment with 4 w/v% calcium thioglycolate were increased remarkably. However, plasma CF level after the co-administration of 0.05 w/v% sodium dodecyl sulfate and 0.1 v/v% 2-mercaptoethanol did not show a considerable difference as compared to that of the case with the presence of the stratum corneum.

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A new peroral test capsule, GA-Test, containing riboflavin (5mg) granules coated with polyvinylacetal diethylaminoacetate (AEA【○!R】) for assessing gastric acidity without intubation was developed and evaluated for usefulness. GA-Test is based on the tracing in the urine of riboflavin, which is released in the stomach only in the presence of acidic fluid and is absorbed. Due to the film coating, riboflavin released very quickly at a pH of less than 5, and not at all at a pH of greater than 6. GA-Test gave a significant correlation, quantitatively, with peroral Gastrotest【○!R】 in assessing acidity, a non-intubation method which had been marketed in Japan prior to 1980. GA-Test results allowed division of the subjects into two groups i.e., subjects having low (hypo-or anacidity) gastric acidity and those having high (normal or hyperacidity) gastric acidity, GA-Test results agreed well with results of intubation (around 91.4% ; 32 out of 35 cases) and were easily reproduced during the evaluation.

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Rat brain adenylate cyclase was solubilized with a combination of 0.7% sodium cholate and 0.6M ammonium sulfate, and fractionated by addition of solid ammonium sulfate. The precipitate at 35% ammonium sulfate saturation contained neither guanine nucleotide-binding regulatory protein (G protein) nor calmodulin, and was used as the catalytic unit of the enzyme system. This catalytic unit was activated synergistically by forskolin and Mn²⁺. An apparent K_m value for Mg-adenosine triphosphate (ATP) of the catalytic unit was about 80 μM in the basal state, while it increased in concurrence with the increase in the enzyme activity when forskolin was added to the assay system. The increase in the K_m value depended on the forskolin concentration up to 1μM, above which the value converged on ca.200μM. Furthermore, activation of the catalytic unit by forskolin was more marked at higher concentration of Mg-ATP. On the other hand, Mg²⁺ suppressed the increase in the K_m value for Mg-ATP by forskolin, though the value in the basal state was not changed by Mn²⁺ alone. These findings indicate that the activation of the catalytic unit by forskolin is accompanied by the change in the affinity for Mg-ATP and Mn²⁺ modifies the change.

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Metabolic disposition of 8α, 9α-and 8β, 9β-epoxyhexahydrocannabinols (EHHCs) was studied using mice to clarify mechanisms which cause a difference in their pharmacological activities. At given time intervals from 0.5 to 60min after intravenous injections of 8, 9-EHHCs (10mg/kg), levels of unchanged epoxides extracted from blood, liver and brain of mice were determined by gas chromatography. Blood levels of both epoxides declined biphasically, and the concentrations of 8α, 9α-EHHC were higher than those of 8β, 9β-EHHC at all the time intervals determined. Biological half-lives in the slower phase were 17 and 13 min, respectively, for 8α, 9α-and 8β, 9β-EHHCs. A similar result was obtained for 8, 9-EHHCs concentrations in the liver. However, no significant difference in the brain levels was found between 8α, 9α-and 8β, 9β-EHHCs. Concentrations of 8α, 9β-and 8β, 9α-dihydroxyhexahydrocannabinols as well as unchanged epoxides 15min after 8, 9-EHHCs injections increased significantly in the liver of mice pretreated with SKF 525-A (25mg/kg, i.p.) comparing with the control. When Δ⁸-tetrahydrocannabinol (Δ⁸-THC), 8α, 9α-or 8β, 9β-EHHC was injected into mice intracerebroventricularly (25μg/head), pentobarbital (40mg/kg, i.p.)-induced sleep prolonging effect was ranked in the following order, 8β, 9β-EHHC>Δ⁸-THC>8α, 9α-EHHC. These results suggest that monooxygenase system involving cytochrome P-450 and epoxide hydrolase together play important roles in the epoxides metabolism. In addition, different activities of 8α, 9α-and 8β, 9β-EHHCs to the central nervous system may cause a difference in their pharmacological effects rather than metabolic factors.

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It was clear that the proportion of high mobility cells in thymus tended to increase during tumor development by cell electrophoresis. Although the antitumor activity of PSK, protein-bound polysaccharide or mitomycin-C was similarly effective in sarcoma-180-bearing mice, the histogram pattern of thymocyte electrophoresis differed markedly from each other. Normally, the proportion of high mobility cells of thymocyte increased more with the administration of mitomycin-C than that of the untreated tumor-bearers, while PSK kept the thymic cell mobility histogram normal. Changes of thymocyte electrophoresis caused by the drugs also correlated with the depression of their antiinfectious activity. Using the fully automated cell electrophoretic instrument, the drug can be evaluated simply from the viewpoint of antiinfectious efficacy.

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We compared the therapeutic effects of various low-molecular-weight enzyme inhibitors on dystrophic mice. Leupeptin, bestatin, forphenicinol and forphenicine significantly affected the enzymatic activities in the dystrophic muscles. The pattern of enzymatic changes in the muscles of forelimb and hindlimb caused by these inhibitors were similar in spite of the variety of their inhibitory spectra in vitro. However, comparing the pattern of enzymatic changes in spleen, forphenicinol differed from the other inhibitors tested. This may be related to the peculiar effects of this inhibitor on immunologically responsive cells.

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Antitumor agent melphalan was conjugated through a carbodiimide-catalyzed reaction to poly (L-lysine) (71.3K and 2K) and poly (L-glutamic acid) (60K and 14K) at a ratio of approximately one molecule per 7-lysyl and 23-glutamate residues, respectively. These conjugates had 40-70% of alkylating activities by themselves in vitro as compared with free melphalan. Poly (glutamic acid) conjugates showed the antitumor activity in vivo against Yoshida sarcoma in rats. In addition, poly (glutamic acid) conjugates containing ³H-phenylalanine which was used as a model compound instead of melphalan had a sustained release property of radioactivity and the release rates could be regulated by exopeptidases. After subcutaneous injection as the first choice of routes of administration, moreover, the conjugates were found to be absorbed through the lymphatic transport system, probably due to the macromolecularity. These results suggest that the melphalan-poly (amino acid) conjugates are one of good candidates to attain the sustained release and targeting of drugs in cancer chemotherapy.

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Induction effect of phenobarbital (80mg/kg, daily for 4d), 3-methylcholanthrene (40mg/kg, daily for 4d), and isosafrole (150mg/kg, daily for 4d), on 2-and 4-hydroxylations of estradiol 17-sulfate by rat liver microsomes with an NADPH-generating system was investigated. On catechol formation from estradiol 17-sulfate, only phenobarbital caused some increase of the 2-hydroxylase activity in both sexes. While 4-hydroxylase activity was caused effectively by phenobarbital and isosafrole in both sexes, especially, the induction by the former in male rats was over six-fold increase to the control.

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Significance of the formation of 4-dimethylamino-3-hydroxymethyl-2-methyl-1-phenyl-3-pyrazolin-5-one (AM-3-CH₂OH) for the metabolism of AM was examined quantitatively in rats. Although urinary excretion of AM-3-CH₂OH accounted for only 0.7% to the dose, incubation of AM in the isolated hepatocyte system resulted in the formation of 9% of AM-3-CH₂OH. Furthermore, metabolic disappearance of AM-3-CH₂OH in the same system was fast, indicating the properties of an intermediate metabolite. These results suggested that the metabolic pathways via AM-3-CH₂OH are very important in the metabolism of AM.

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