Pharmacokinetics and bioavailability for the 1-benzenesulfonylhydantoin derivatives and 1-unsubstituted hydantoin derivatives were evaluated from the plasma concentrations after oral and intravenous administrations to dogs. Apparent volume of distribution of the 1-benzenesulfonylhydantoin derivatives was about 0.25 l/kg, while that of the 1-unsubstituted hydantoin derivatives was about 1.3 l/kg. The result suggests that introduction of the benzenesulfonyl group at 1-position of the hydantoin ring has marked effect on the distribution into the fluids and tissues of the body. Bioavailabilities of sodium 5, 5-diphenylhydantoin and sodium 1-benzenesulfonyl-5, 5-diphenylhydantoin exceeded those of their corresponding free forms. The results were well explicable in terms of the excellent dissolution behaviors of the salt forms. The bioavailabilities of 5-ethyl-5-phenylhydantoin and 1-benzenesulfonyl-5-ethyl-5-phenylhydantoin were almost perfect. The results suggest that the dissolution rate is a rate-determining step in the bioavailability of the derivatives having two phenyl groups at 5-position of the hydantoin ring, irrespective of the presence of the benzenesulfonyl group at 1-position.

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Effect of islet-activating protein (IAP) on glucose utilization of peripheral tissues and glycogen synthesis of the liver was investigated in diabetic KK mice. The ¹⁴C-content of diaphragm glycogen following the injection of [U-¹⁴C] glucose was much less in KK mice than in dd/Y mice, and it was restored to normal in KK mice treated with IAP. The enhanced glucose utilization in these mice was completely abolished by the injection of anti-insulin serum. Glycogen synthesis of the liver after glucose load was also less in KK mice than in dd/Y mice, and it was clearly suppressed in both groups of mice by IAP treatment. It was concluded that improved glucose tolerance of IAP-treated KK mice was mostly due to enhanced glucose utilization of peripheral tissues secondary to increased insulin secretion induced by IAP injection.

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It was investigated as to whether a spontaneous reactivation was also observed in fenitro-oxon-inhibited plasma cholinesterase (ChE) of human and several animals, such as mice, guinea pigs and rabbits, as previously reported in rat plasma ChE. It was found from the results that a marked spontaneous reactivation took place during storage at 37°C or 24°C in all of human and the animals, while these reactivations of animals were to some extent slower and slighter than that of rat. Moreover, there was little significant difference between the spontaneous reactivations observed in using acetylthiocholine and butyrylthiocholine as a substrate, although the use of the latter substrate resulted in somewhat faster and greater spontaneous reactivation only in rat. These results suggest that the spontaneous reactivation takes place in plasma pseudo ChE of various animals after inhibition with fenitro-oxon.

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To determine whether concentrations of trimethadione (TMO) and its metabolite 5, 5-dimethyl-2, 4-oxazolidinedione (DMO) in plasma as well as in urine of rats are useful indicator of drug-metabolizing capacity or not, the following experiments were carried out. Plasma TMO and DMO concentrations were measured in phenobarbital (PB) or 3-methylcholanthrene (3-MC)-pretreated rats following the administration of TMO. In PB-pretreated rats, there was a good correlation between elimination rate constant (K_el and plasma DMO/TMO ratio ; r=0.991 at 1 h, r=0.967 at 2 h). However, there was no good correlation in 3-MC-pretreated rats (r=0.780 at 1 h, r=0.720 at 2 h). TMO and DMO excretion in PB and 3-MC pretreated rats following the administration of TMO were not significantly different in 24-h urine. These experiments, together with the previous findings, indicate that concentrations of TMO and DMO in plasma, but not in urine, in PB-pretreated rats may be a useful indicator of drug-metabolizing capacity.

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In order to resolve the mechanism of taurine-induced enhancement of drug absorption, the effect of ionic components of the luminal solutions on drug absorption was examined by using the loop of rat stomach in situ. K⁺ has its remarkable influence on the control values of aspirin absorption. The control values, at and above 25 mM already reached to a nearly corresponding degree as that of taurine-induced enhancement, resulting in apparent disappearance of enhancement effect. On the other hand, the action of taurine on salicylamide absorption is revealed to be K⁺ concentration-dependent, whereas all the control values remain fairly constant. Moreover, at the higher concentration of 10 mM, aspirin absorption turned out to be significantly inhibited in the presence of taurine, and this finding is supposed to be attributed to the protection of taurine against aspirin-induced gastric mucosal damage. On the contrary, salicylamide absorption was greatly enhanced. All these results clearly support that the mechanism of action of taurine toward both drugs should be separately considered.

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The absorption, distribution and elimination of creatinine and urea, which are considered to pass through the water-filled pores of biological membranes easily, were investigated in hyperthyroid mice to clarify the effects of enhanced blood circulation rate on drug behaviour in the body. The elimination rate constant in hyperthyroid mice was significantly and considerably larger than that in the control in both creatinine and urea (p<0.01). This result might be based on the increased urinary excretion rate of these two chemicals in hyperthyroid mice. The result of autoradiographic study indicated that creatinine was distributed more homogeneously in hyperthyroid mice than the control at 30 s and 2 min following intravenous administration. It was probably caused by the enhanced membrane permeability to creatinine due to some physiological changes (e.g. blood flow rate and pressure) or to a change of membrane itself. The gastrointestinal absorption of these two chemicals were also evaluated by the expiratory excretion of ¹⁴CO₂ following oral administration. The results suggested that creatinine might be absorbed more slowly in hyperthyroid mice than in the control, and that in the case of urea such a difference in absorption might not exist.

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The bioavailabilities of flufenamic acid (I) from a commercial aluminum flufenamate (II) tablet and I capsule were estimated by measuring urinary excretion of I and its metabolites fluorometrically. The dissolution rates of I from both dosage forms were also determined. The effects of concomitant intake of food or antacid on the bioavailabilities from the II tablet and the I capsule were investigated. The extent on I bioavailability from the II tablet was less than 30% of that from the I capsule. Dissolution tests suggested that the low bioavailability of I from II tablet resulted from the extremely slow release of I from the II complex. Intake of a standard meal retarded I absorption from I capsule, but did not affect that from the II tablet. Ingestion of dried aluminum hydroxide gel granules had little effect on I bioavailability from the I capsule.

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Fusarenon-X (F-X) is one of the trichothecene mycotoxins. F-X enhanced D-xylose absorption rate in rat everted intestinal sac. In the present work, the mechanism of the F-X-induced enhancement of intestinal D-xylose absorption rate was studied. F-X had no detectable effect on D-glucose absorption of everted rat intestine. When 10 mM of D-xylose was employed, a concomitant application of oxygen-free condition and low temperature failed to affect the D-xylose absorption of normal rat, but inhibited that of F-X-treated rat. When D-glucose concentration was 5 mM, the concomitant application of oxygen-free condition and low temperature depressed the D-glucose absorption of normal rat, while it did not reduce that in F-X-treated rat. These results suggested that the sugar translocation mechanism of F-X-treated rat intestine was different from that of normal one. F-X-induced enhancement of D-xylose absorption in everted intestinal sac may depend on the increase in permeability of the intestinal membrane which is derived from the histological and functional damage of the intestinal mucosa induced by F-X.

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Local and systemic anti-inflammatory effects of topically applied flunisolide on hind footpad edema induced by subplantar injection of 1 μg of serotonin in mice were evaluated in comparison with those of three related steroids. The order of the potency for local anti-inflammatory effect observed in the foot injected with the steroids was flunisolide, dexamethasone, betamethasone valerate and beclomethasone dipropionate in decreasing order. In contrast, potency for systemic effect of flunisolide observed on the opposite foot was rather weak compared with its strong local effect. When steroids were administered orally, the order of the anti-inflammatory potency was dexamethasone, beclomethasone dipropionate, flunisolide and betamethasone valerate in decreasing order. All of the data demonstrate that flunisolide is highly active in topical use, while systemically it is relatively weak, especially by oral administration. Those characteristics of flunisolide could be attributable to its rapid metabolic inactivation in the liver, which suggests a great advantage of its topical use in the clinical medicine.

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Antitumor activity of 15 1-acyloxymethyl derivatives of 5-fluorouracil was examined by both intraperitoneal injection and oral administration in L1210 leukemia system. Therapeutic ratio for dodecanoyloxymethyl derivative by intraperitoneal injection was 23 which was greater than that for 5-fluorouracil (11). On the other hand, undecanoyloxymethyl derivative of 5-fluorouracil showed the highest therapeutic ratio (5. 8) when administered orally which was greater than that for 5-fluorouracil (1.9) and 1-(2-tetrahydrofuryl)-5-fluorouracil (1.0).

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