We examined the interaction of morphine-epoxide, which was assumed to be a new metabolite of morphine, with opiate receptor subtypes using pharmacological and biochemical techniques. Morphine-epoxide was about 3 to 4 times less potent than morphine to the interactions of opiate receptors. However, the ratio of IC₅₀ values for the guinea pig ileum and mouse vas deferens to electrical field stimulation and the ratio of IC₅₀ values for the [³H]-dihydromorphine and [³H]-D-ala²-D-leu⁵ enkephalin binding to rat brain membrane preparations of morphine-epoxide was similar to those of morphine. Morphine-epoxide had virtually no effect on the twitch responses of rabbit and rat vas deferens. Furthermore, "sodium ratio" and "GTP ratio" of morphine-epoxide were similar to those of morphine and differed from naloxone. These results suggest that morphine-epoxide as well as morphine behaves as the agonist on the mu type opiate receptor notwithstanding that the affinity of morphine-epoxide is slightly less than that of morphine.

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The transport mechanisms of cephalexin (CEX) and ampicillin (AB-PC) across rat jejunum were examined using the electrophysiological technique in vitro. From the experiments under the short-circuit condition, it became evident that the specific transport system participates in the mucosal-to-serosal transport of CEX, while AB-PC is transported only by the simple diffusion. In addition, the transport routes of these drugs were examined using the voltage-clamp technique. Salicylate, a model drug of the weak electrolyte, was transported mainly via a paracellular route, while CEX, in the absence of Na, penetrated the membrane viatwo routes, i.e. the transcellular route and the paracellular route. Similar result was obtained as to AB-PC. So it seems to be likely that these two drugs diffuse through the intestinal epithelium via the similar pathways in the Na-free condition.

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The sulfur-containing metabolites of m-dichlorobenzene (m-DCB) were identified by using gas chromatography-mass spectrometry and disposition of these metabolites was studied. In the blood, urine and feces of rats dosed with m-DCB, 2, 4-and 3, 5-dichlorophenyl methyl sulfoxides and 3, 5-and 2, 4-dichlorophenyl methyl sulfones emerged, while their possible precursors, 3, 5-and 2, 4-dichlorophenyl methyl sulfides (Me' and Mf', respectively), were not detected in the blood, urine and feces. However, after heating the alkalinized urine and feces, the methyl sulfides appeared. Each cumulative amount of the methyl sulfoxides and methyl sulfones excreted in both the urine and feces for 120 h was less than 0.3% of the dose, while the amounts of Me' and Mf' excreted were about 0.9 and 0.2%, respectively. The amounts of 2, 4-and 3, 5-dichlorophenyl mercapturic acids excreted in the urine were 2.3 and 1.2%, respectively. However, the former was increased to 27.3% and the latter to 4.3% after heating the acidified urine. The cystein conjugates were not detected. The administration of m-DCB decreased the glutathione level in liver of fasted rats but it was not further reduced by diethyl maleate (DEM)-pretreatment. The kidney glutathione level was not altered by the administration of m-DCB. The blood level of methyl sulfoxides and methyl sulfones and their excretion in urine were markedly decreased in DEM-pretreated rats, while the mercapturic acids in acid-treated urine of DEM-pretreated rats were not significantly decreased. These results suggest that the methyl sulfoxides and methyl sulfones were derived from glutathione in liver and the formation process of mercapturic acids was somewhat different from that of methyl sulfoxides and methyl sulfones.

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The in situ single-pass perfusion method in an individual rat was developed to discuss the solvent drag in drug intestinal absorption without the individual differences. In this method the apparent water influx (influx') was used as a measure of solvent drag in the same manner as the previous paper¹⁾. Consequently the sieving coefficients of salicylic acid and antipyrine in one rat are not significantly different from one but in the other are significantly smaller than one, resulting in 0.6-0.7 in average. And it was also shown that the reflection from the membrane in the solvent drag can be detected more precisely and efficiently by this method than the recirculating method in the previous paper. The D₂O absorption clearance (CL_D2O was equal to net water flux as estimated theoretically when the D₂O concentration in lumen was equal to that in plasma, indicating that D₂O can be absorbed by water absorption even in the absence of the concentration gradient. Estimating the real water influx from the net water flux obtained under such condition, the minimal contribution ratio of the solvent drag to the total absorption clearance of salicylic acid and antipyrine was calculated to be approximately 12%.

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In vitro metabolism of Δ⁹-and Δ⁸-tettahydrocannabinols (THCs) was studied using human liver microsomes. Δ⁹-orΔ⁸-THC was incubated with microsomes in the presence of NADPH-generating system. The metabolites formed were extracted with ethyl acetate, separated by preparative thin-layer chromatography, and identified as trimethylsilyl derivatives by gas chromatography-mass spectrometry. 9α, 10α-Epoxyhexahydrocannabinol (EHHC) together with four monohydroxylated metabolites was formed from Δ⁹-THC. The epoxide was found to resist the hydrolysis by epoxide hydrolase, and was further converted to several metabolites by monooxygenase system involving cytochrome P-450. On the other hand, 8β, 9α-dihydroxyhexahydrocannabinol (diOH-HHC) instead of epoxy metabolites was formed from Δ⁸-THC under the conditions for monooxygenase. When 1, 1, 1-trichloropropene-2, 3-oxide was further added to the incubation mixture, both of 8α, 9α- and 8β, 9β-EHHCs were found to be formed from Δ⁸-THC. These epoxides of Δ⁸-THC were preferentially hydrolyzed to 8β, 9α-diOH-HHC by epoxide hydrolase. These results indicate that 9α, 10α-EHHC formed from Δ⁹-THC is further metabolized not by epoxide hydrolase but by monooxygenase system involving cytochrome P-450, and that, on the contrary, 8α, 9α-and 8β, 9β-EHHCs derived from Δ⁸-THC may be metabolized by epoxide hydrolase rather than cytochrome P-450 in the human liver, forming 8β, 9α-diOH-HHC.

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Effect of a steroidal alkaloid, epipachysamine-A, extracted from Pachysandra terminalis SIEB. et ZUCC. on gastric acid secretion was studied in rats. Epipachysamine-A prevented 2-deoxy-D-glucose-or thyrotropin-releasing hormone-stimulated gastric acid secretion in anesthetized rats. However, the compound did not influence bethanechol-or electrical vagal stimulation-induced gastric acid secretion. These results suggest that the effect of epipachysamine-A is due to the influence on the central nervous regulatory mechanism in the gastric acid secretion.

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