The tissue distribution mechanism of adriamycin (ADR), its relatives, daunomycin (DNR), adriamycinol (ADR-ol), daunorubicinol (DNR-ol) and actinomycin D (ACT-D) has been studied in rats and rabbits. The following evidences with respect to tissue dustribution of ADR were obtained : 1) remarkable binding of ADR to tissue homogenate, 2) significant difference in the tissue binding of ADR among tissues, 3) exclusive localization of ADR in cell nucleus, 4) good correlation between the tissue binding of ADR and the tissue desoxyribonucleic acid (DNA) concentration, 5) comparatively good coincidence between the experimentally determined tissue binding of ADR and that calculated from in vitro nuclear binding parameters reported and the tissue DNA concentration, and 6) no correlation between the concentration of tissue phospholipids (i.e. cardiolipin, acidic phospholipids and total phospholipids) and the K_p value of ADR in rats. From these findings, it was confirmed that the nuclear binding is a determinant of the extensive tissue distribution of ADR and that a remarkable variation in the tissue concentration of ADR is due mainly to the difference in the tissue DNA concentration. Furthermore, good correlations were demonstrated between the DNA concentration and Kp_app values of DNR and ACT-D in rats and DNR, ADR-ol and DNR-ol in rabbits. Hence, it is suggested that there is a common mechanism of in vivo tissue distribution of ADR and its relatives which can intercalate to DNA and the determinant of characteristic tissue distribution is nuclear binding of these antibiotics.

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The rectal absorption of pepleomycin sulfate (PEPS) in rats was increased significantly by the coadministration with each of diclofenac (DC), sodium 5-methoxysalicylate (5-MSA) and phenylalanine enamine of ethylacetoacetate (Enamine). 5-MSA increased the lymphatic uptake of PEPS after rectal administration while DC and Enamine did not. The mechanism behind the enhancing action of 5-MSA on the lymphatic uptake of PEPS may be due to the suppressing action of 5-MSA on the vascular permeability to PEPS. DC increased the vascular permeability to PEPS but Enamine did not affect it. Findings obtained in this study may indicate that adjuvant used acts independently at the rectal mucosal membrane and at the vascular membrane for membrane for membrane permeability to PEPS.

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The potency of seven phenoxyacetic acid derivatives to induce microsomal stearoyl-CoA desaturation activity in rat liver was compared with that of 2-(4-chlorphenoxy)-2-methy-propionic acid (clofibric acid). These compounds were given to rats with diet. Of seven phenoxyacetic acid derivatives tested, both 2-(4-chlorophenoxy)-propionic acid and 2-(2-chlorophenoxy)-2-methyl-propionic acid increased considerably the desaturation activity as was observed with clofibric acid. Moreover, 2, 4, 5-trichlorphenoxyacetic acid (2, 4, 5-T) also increased the desaturation activity, although the inducing effect on desaturation activity was very weak compared to that of clofibric acid. These three compounds increased activity of terminal desaturase without accompanying marked changes in reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b₅ reductase activity and cytochrome b₅ content as was the case with clofibric acid. The other four phenoxyacetic acid derivatives, 2-(phenoxy)-propionic acid, 4-chloropphenoxyacetic acid, 2-chlorophenoxyacetic acid and 2, 4-dichlorophenoxyacetic acid (2, 4-D) changed scarcely the desaturation activity. These compounds had no influence on NADH-cytochrome b₅ reductase activity, cytochrome b₅ content and terminal desaturase activity. Correlating with the changes in the desaturation activity, concentration of octadecenoic acid was increased in hepatic microsomes, whole liver and serum. Treatment with clofibric acid did not change the concentration of octadecenoic acid in brain, lung, heart, spleen, testis and adipose tissue.

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The salivary excretion of urea was investigated by collecting parotid saliva (Pr) and mandibular-sublingual saliva (MS) separately in beagle dogs. (1) After intravenous administration of urea (1.5g/kg), urea concentrations in both Pr and MS were well correlated to but were lower than those in plasma. Urea concentrations in MS were significantly lower than those in Pr (p<0.05), indicating that there was glandular difference in salivary excretion of urea. (2) This glandular difference was not explained by Matin's equation, even if all variation factors in this equation were considered. (3) At relatively low salivary flow rates, the increase in saliva/plasma urea concentration ratio (S/P ratio) for both Pr and MS was found in the experiments for endogenous urea. (4) At relatively low salivary flow rates, glandular difference was observed in the S/P ratios of sodium ion. (5) Salivary clearance of urea was highly dependent on salivary flow rate under stimulated condition for salivation, and mean value of the salivary clearance of urea was about 20% of its total body clearance.

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Intraduodenal administration of 70% MeOH extract of Japanese Angelica root (3g/kg) and Peony root (3g/kg) increased uterine contractile activities in anesthetized rabbits. The activities of both extracts shifted to the aqueous layer (positive at a dose of 1g/kg) with successive fractionation of the extracts with hexane and BuOH, indicating contribution of a hydrophilic principle(s) to the effect. In some animal preparations, inhibiting effect of the extracts on uterine contraction was noted after the uterotonic effect terminated. The aqueous fraction (40mg/kg) after being treated with hexane and BuOH also produced uterine contraction along with decrease of blood pressure through i.v. route, which was greatly inhibited by pretreatment of atropine, suggesting participation of cholinergic components in the effect of both extracts.

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The present study was undertaken to compare the peculiarity of enzymatic changes in dystrophic hamsters and mice. Various enzymatic activities in muscle, bone, heart, spleen, liver and kidney were measured. The enzymes tested include 7 aminopeptidases, 5 endopeptidases, 3 glycosidases, creatine kinase, phosphatase and esterase. In dystrophic mice, the enzymatic changes were chiefly confined to muscle and bone. In dystrophic hamsters, on the other hand, extensive and pronounced changes in enzymatic activities were seen not only in skeletal muscle but also in bone, heart muscle, spleen, liver and kidney. Furthermore, resemblance of pattern of enzymatic changes was seen among several organs including skeletal muscle, heart muscle, bone and spleen in the hamster model. Comparing the enzymatic changes in these two models, dystrophic mouse may be regarded as more specific a model for musculoskeletal diseases. Dystrophic hamster may be related more to multiorgan diseases possibly associated with immunological or other systemic diseases. These models may represent two different disease categories, respectively.

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We investigated the spontaneous reactivation of mouse plasma cholinesterase (ChE) after inhibition by various organophosphorus compounds. The remarkable spontaneous reactivations during storage at 24°C were observed in plasma ChE prepared 30 min after oral administration of three O, O-dimethyl organophosphorus compounds, i.e. malathion, methyl-parathion and cyanox ; while the spontaneous reactivation did not occur after inhibition by tolclofos-methyl, one of O, O-dimethyl organophosphorus compounds. The plasma ChEs inhibited by surecide, salithion and leptophos, which contain no O, O-dimethyl moiety, were not reactivated or only slightly so. These results suggest that a more sufficient attention should be paid in the determination of activity of plasma ChE inhibited by O, O-dimethyl organophosphorus compounds than that of plasma ChE inhibited by organophosphorus compounds without O, O-dimethyl moiety, since plasma ChE inhibited by the organophosphorus compounds with O, O-dimethyl moiety, except for tolclofos-methyl, was more easily reactivated, and the correct activity of inhibited plasma ChE can not be obtained without attention to the spontaneous reactivation. Furthermore, these spontaneous reactivations were examined by using butyrylthiocholine as well as acetylthiocholine as a substrate, and results showed that there was little difference between the spontaneous reactivations observed in using acetylthiocholine and butyrylthiocholine. So, it is concluded that these spontaneous reactivations take place only in pseudo ChE.

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There have been significant correlations between serum concentration ratios of 5, 5-dimethyl-2, 4-oxazolidinedione (Dimethadione, DMO) /trimethadione (TMO) after administration of TMO and hepatic microsomal cytochrome P-450 contents in rats with various treatments (CCl₄ or phenobarbital). The pharmacokinetics of TMO and DMO, and the serum concentration ratio of DMO/TMO have been investigated in healthy volunteers after oral administration of 1mg/kg (N=4), 2mg/kg (N=6) and 4mg/kg (N=6) TMO, respectively. TMO and DMO concentrations in serum were determined by a gas-liquid chromatographic method. Serum disappearance of TMO was described by one compartment model. The T_1/2, K_el, V_d and C1 of TMO and of DMO were shown to have almost the same values in 2mg/kg or 4mg/kg TMO administration. Correlation coefficient between DMO/TMO ratio in serum and time course after 1mg/kg, 2mg/kg and 4mg/kg TMO administration was found to be r=0.958, r=0.924 and r=0.938, respectively. These results indicate that the serum concentration ratio of DMO/TMO, especially at 2 or 4 h after 4mg/kg TMO administration orally, may be an index of hepatic drug-metabolizing capacity in human serum as well as in rats.

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The effects of a new analgesic drug, ciramadol, on single neuronal activities of lamina V-type celles of the spinal dorsal horn were investigated in spinal rats when applied microelectrophoretically to the cells or administered systemically. In the majority of lamina V-type cells examined, ciramadol inhibited the activities induced by intra-arterial injection of bradykinin (painful stimulation) but not those induced by mechanical noxious and innocuous stimuli. These results directly evidence that ciramadol acts on the lamina V-type cells of the spinal dorsal horn to block the bradykinin-induced (nociceptive) activities there.

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The present studies were conducted to further investigate a role of cyclic nucleotides for organic anion transport in rat kidney cortical slices by using papaverine as a phosphodiesterase inhibitor. Papaverine was chosen for this study because this drug is an organic cation, a transport system of which is thought to be clearly separable from an organic anion transport system. Papaverine inhibited not only p-aminohippuric acid (PAH) accumulation in the slices but also urate one. Pretreatment of the slices with papaverine was effective for significant inhibition of PAH accumulation during subsequent incubation in the absence of papaverine. The present results suggest that a relationship may exist between cyclic nucleotides and organic anion transport in rat kidney cortical slices, although further work is necessary before the above evaluation can be given.

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Effect of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a calmodulin-antagonist, on renin release was examined using rat kidney cortical slices. Although the amounts of renin release from the slices were stable during incubation of 3 consecutive 15 min periods in Krebs-Ringer bicarbonate solution (pH 7.4), the addition of W-7 to the incubation medium resulted in a concentration-dependent increase in renin release from the slices. The stimulant effect of W-7 on renin release was abolished by the removal of calcium from the incubation medium. These results suggest that the inhibition of the calcium-calmodulin system leads to the stimulation of renin release from rat kidney cortical slices.

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