Colchicine, a microtubles-disrupting agent, when injected into subplantar region of the hind paw of rats, provoked an immediate elevation of the permeability of local vascular networks, resulting in a local tissue edema. The extent of the edema was dose-dependent. It was not affected at all by pretreatment of the rats with cyproheptadine, while cyproheptadine almost completely blocked formation of serotonin edema. When colchicine was applied together with serotonin, a synergistic enhancement of edema formation was observed. Colchicine and histamine were also synergistic.

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The distribution of 1-hexylcarbamoyl-5-fluorouracil-6-¹⁴C (HCFU) and 5-fluorouracil-6-¹⁴C (5FU) was studied in mice following a single oral administration. When HCFU and 5FU were given orally to mice, they were readily absorbed from the gastrointestinal tract and the radioactivity was detected in various tissues and organs. Highest radioactivity after administration of HCFU was shown in the liver, kidneys, stomach wall and plasma, followed by the lungs, and adrenals. On the other hand, highest radioactivity after administration of 5FU was exhibited in the liver, myocardium, lungs, pancreas, spleen, kidneys, adrenals and gastro-intestinal wall. Distribution pattern and disppearance of HCFU were similar to those of 5FU. Marked difference in the distribution between HCFU and 5FU was detected only in the gastro-intestinal wall, namely, HCFU was retained for a long period in the stomach wall while 5FU did in the intestinal wall.

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S-Adenosyl-3-thiopropylamine (ATPA) damaged all three cell lines examined. The toxic effect was dependent on the kind of serum added in the culture medium. The serum dependency was closely related to the monoamine oxidase activity in the serum. ATPA was significantly oxidized in the calf serum which is rich in the enzyme activity. Detection of acrolein, a potent cytotoxic aldehyde, from incubation mixtures containing ATPA and calf or horse serum supported a hypothesis that release of acrolein from oxidized ATPA may be responsible for the toxic effect of ATPA.

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Intrabiliary retrograde infusion of a fluorescent sulfhydryl reagent, N-[p-(2-benzimidazolyl) phenyl] maleimide (BIPM), to rats reduced the concentration in bile and the bile/liver concentration ratio of acetyl procainamide ethobromide (APAEB) to about a half of the control. The reagent is speculated to inhibit the active excretory process by binding to sulfhydryl groups of proteins involved in the active transport. By gel filtration on a Sephadex G-75 column of the bile sample collected after infusion of BIPM and Triton X-100 solution successively to rats, BIPM was found to be bound to proteins which did not occur in the normal bile. Polyacrylamide gel electrophoresis of the same sample showed that BIPM was bound to the major protein band in the gel. The binding of BIPM to the proteins occurred not only by infusion of BIPM in vivo but by addition of BIPM in vitro to the bile after treatment with Triton X-100. When APAEB or neutral red, an organic cation, was injected to rats before the treatment with Triton X-100, binding to the major band proteins of BIPM added to the bile sample was much depressed ; N-ethylmaleimide, PCMBS or iodoacetamide, a sulfhydryl reagent, also reduced the binding when infused retrogradely before the treatment with Triton X-100. The results of this experiment indicate that the major band proteins solubilized with Triton X-100 might be involved in the active transport of organic cations as BIPM was bound to the band and the binding was reduced by the pretreatment with organic cations and other sulfhydryl reagents.

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The lyophilized crude scorpion venom from Heterometrus gravimanus was administered to anesthetized cats, and the changes in electrocardiogram, hypotensive effect, increase in the depth of respiration and blood flow were observed. From the pharmacological experiment on isolated guinea pig ileums, the presence of both acetylcholine-and histamine-like substances was suggested in the crude venom. Acetylcholine-like substance was compared with an authentic acetylcholine on the silicagel thin-layer chromatography, and the amount was estimated to be 8-15 μg equivalent to acetylcholine per mg venom by the Magnus method. Histamine-like substance was extracted and purified from the crude venom, and was run on both silicagel and polyamide thin-layer chromatographies concurrently with an authentic histamine and 5-hydroxytryptamine. By both bioassay with isolated guinea pig ileum and chemical determination with the fluorometric methods, the content of histamine-like substance was calculated to be about 30 μg equivalent to histamine per mg venom. 5-Hydroxytryptamine was not found. Hemolytic action was observed in the human erythrocytes with the venom and the maximal action was found at pH 5.5.

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Apparent partition coefficient (P') for methylene blue (MB) in n-heptane/phosphate buffer (pH 7.4) system and apparent volumes of distribution (V_d') for MB and chlordiazepoxide (CDP) in rabbits were determined. CDP is one of the basic drugs in the region of low P'. Although P'for MB also has a low value (0.0186), V_d, for MB (21.0 l/kg) was higher than that for CDP (1.96 l/kg). This fact could not be explained by the previously proposed model for V_d'-P' relationship which stated that V_d'should have an almost constant value in the region of low P'and required more elaborated model that includes factors other than partition coefficient. Therefore, drug transfer to erythrocyte-fraction for these two drugs was investigated in vivo and in vitro, and protein binding of MB was determined in vitro. Transfer to erythrocytefraction for MB was higher than that for CDP both in vivo and in vitro. Transfer to erythrocytefraction for MB was higher than that for CDP both in vivo and in vitro. However, these results only partly accounted for the high value of V_d'for MB. The extent of binding of MB to bovine serum albumin was comparable to those of other drugs with low P', CDP and antipyrine. Hence, it was considered that protein binding did not contribute to a high V_d' value for MB. These evidences suggest that there may be an interaction between MB and some biological components excluding such protein as BSA in the body.

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Enhancement of the lymphatic transport of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), an orally active anticancer agent, was demonstrated by the administration of W/O emulsion into the loop of rat small intestine. The lymphatic transport of FT-207 was inhibited by the presence of bile. Absorption of oil in the absence of bile was confirmed by light microscopy. Electron micrograph revealed that oil droplets are mainly transported via the lymphatic system.

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A novel method for evaluation of oral lipid formulation in rats, which enabled us to reduce the dose level to 2 mcl/rat with satisfactory acuracy, was presented. The dose level was fairly comparable to that of clinical unit dose such as a soft capsule on mcl/kg (lipid dose/body weight) basis. By using this method, lipid-containing oral dosage forms were evaluated. A new antiinflammatory agent 1-cyclopropyl-4-phenyl-6-chlor-2(1H)-quinazolinone (SL-512) was selected as a model of poorly water soluble drug. A medium chain triglyceride was mostly used as a lipid vehicle. It was demonstrated that the characteristics of the lipid formulation could be estimated by measuring the gastric emptying rate of the drug or sometime combined with the intestinal remaining of the drug in rats. These results basically consisted of those obtained from 20 mcl/rat dosing experiments previously reported. It was newly found that by reducing the dose level to 2 mcl/rat, the drug absorption was less affected by the dosage form factors such as the drug concentration in the preparation or the digestibility of lipid vehicle. It was also shown by this method that compared with an aqueous suspension, the drug absorption of the lipid formulation was less variable and less affected by the concomitant food intake.

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The effect of baclofen on static γ-activity enhanced by pinna pinching was compared with some of centrally acting muscle relaxants (chlorpromazine, mephenesin and diazepam) in the anesthetized rat. Baclofen (0.5-2 mg/kg, i.v.) showed only a little effect on the static γ-activity. At a higher dose of 5 mg/kg, the drug showed a marked depressant effect on the static γ-activity, although this dose was much higher than that required to depress spinal reflex activity. On the other hand, chlorpromazine, mephenesin and diazepam depressed the static γ-activity at lower doses than those required to depress spinal reflex activity. From these results, it is concluded that the depressant action of baclofen on the static γ-activity has only a little contribution to the muscle relaxant action and therapeutic effectiveness of the drug.

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