In order to investigate the in vivo first-pass metabolism of acetaminophen (AAP) following the oral and intraduodenal administration in rats, a pharmacokinetic compartment model including absorption process was developed. Using the parameters for the disposition kinetics of AAP and its metabolites, sulfate and glucuronide, which were determined in the separate study, the extent of the first-pass metabolism and the contribution of sulfation and glucuronidation to the total first-pass metabolism in vivo were quantitatively estimated. As for the results, the first-pass metabolism of AAP following the oral and intraduodenal administration ws mainly attributable to the sulfoconjugation pathway in rats. The sulfation of AAP in the intestine and/or in the liver during the first-pass was proved to be a saturable process. Then, the sulfation in the first-pass metabolism showed the dose-and absorption rate-dependent kinetics. Thus, the pharmacokinetic model including the absorption process proposed in the present study was proved to be valid and useful for the estimation of in vivo first-pass metabolism of AAP in rats.

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Ketoconazole (KCZ), an imidazole-containing antimycotic, has been demonstrated to inhibit testosterone biosynthesis in man. In this study, the inhibitory activities of various imidazole drugs such as miconazole (MCZ), cimetidine (CIM), ozagrel (OZA) and its metabolites (M-1 and M-2) on the pathway of testosterone biosynthesis in testicular microsomes were compared with that of KCZ in vitro. Additionally, the changes in serum testosterone level in the patients by the treatments with MCZ were followed. KCZ inhibited 17α-hydroxylase and C^{17, 20}-lyase activities in a dose-depentent manner, while it did not affect 17β-hydroxysteroid dehydrogenase activity. Although the patterns of the inhibitory actions and the interaction of either imidazole drugs with cytochrome P-450 as 17α-hydroxylase and C_{17, 20}-lyase were similar to those of KCZ, the inhibitory potencies and affinities for the cytochrome P-450 system decreased in the order of KCZ>MCZ>OZA>M-2>M-1>CIM. At the end of the intravenous injection of 200 mg MCZ to the patients, the serum testosterone levels decreased by about 16% of the original level and then returned to the original level 5h after the end of injection. These results indicate that either imidazole drugs tested colud inhibit a cuytochrome P-450 enzyme C_{17, 20}-lyase mainly in testicular microsomes, and suggest that MCZ, a potent inhibitor subsequent to KCZ, induces a slight alteration in the testosterone biosynthesis in its clinical use.

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Cinnamic acid inhibits the O^-₂-generating response of guinea pig peritoneal macrophages elicited with a chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (fMLP), but not those with ovalbumin complex of immunoglobulin G₂ antibody and phorbol-myristate acetate. ¹⁾During the course of study on the inhibitory mechanism of cinnamic acid, we found that the acid also inhibited the Ca²⁺ mobilization elicited with fMLP, but not that with the immune complex. In addition, the treatment of macrophages with Ionomycin and ethyleneglycol bis-(β-aminoethylether)-N, N'-tetraacetic acid for depletion of the intracellular Ca²⁺ inactivated completely the O^-₂generation elicited with fMLP, but not its counterpart of the immune complex. Thus, the inhibitory activity of cinnamic acid on the O^-₂generation elicited with fMLP seems partly due to that on the Ca²⁺ mobilization. On the other hand, cinnamic acid augmented the intracellular accumulation of adenosine 3', 5'-cyclic monophosphate (cyclic AMP) in the presence of 3-isobutyl 1-methylxanthine (IBMX), and elevated more intensively the concentration of cyclic AMP when macrophages were stimulated with fMLP. Since IBMC inhibited the O^-₂generation elicited with fMLP, the enhancement of activation of an adenylate cuclase by cinnamic acid might cause depression of the O^-₂generation. This possibility, however, seems to be excluded by the fact that the same effect of cinnamic acid was observed even when macrophages were stimulated with the immune complex.

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The blood-brain barrier (BBB) transport system for choline and basic drugs was characterized by the in vivo carotid artery injection technique (Oldendorf, Brain Res., 24, 372-376, 1970) and in vitro uptake into isolated bovine brain capillaries (Pardridge et al., J. Neurochem. 44, 1178-1184, 1985). Basic drugs such as eperisone, thiamine and scopolamine significantly inhibited choline uptake by the BBB with the half inhibitory concentration, IC₅₀ value of 1.45, 2.06, and 0.47 mM, respectively. On the contrary, the uptake of choline was not inhibited by amino acids (L-phenylalanine and L-arginine) and acidic drugs (nicotinic acid, salicylic acid and valproic acid). Choline was taken up by the isolated brain capillaries in concentration and temperature dependent manners. The uptake of choline by the isolated bovine brain capillaries was significantly inhibited by eperisone, scopiolamine and thiamine in consistent with the in vivo results. Furthermore, eperisone inhibited competitively the yptake of choline with the inhibition constant, K_i value of 455μM. According to these results it was suggested that in the BBB choline and basic drugs would share a common carrier-mediated transport system.

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We isolated eight bacterial strains which could hydrolyze glycyrrhizin to glycyrrhezic acid. The bacterial strains were identified as three strains of Pseudomonas saccharophila, two of Plesiomonas sp., one of Pseudomonas stutzeri, one of Klebsiella pneumoniae subsp. ozaenae and one of Kluyvera ascorbata. Their capacity for the conversion of glycyrrhizin to glycyrrhezic acid was assayed by high performance liquid chromatography. P.saccharophila 11 was the most effective among the eight strains. Then, β-glucuronidase, which is respondible for hydrolysis of glycyrrhizin, activity was assayed with p-nitrophenyl-β-D-glucuronide as a substrate. P.saccharophila 11 showed the highest β-glucuronidase activity among the eight strains. This indicates that P.saccharophila 11 may be useful for production of glycyrrhezic acid from glycyrrhizin by industrial fermentation.

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The quantitative relationship between a drug disposition and the pharmacological effect was examined in rats using chlorzoxazone (CZX), a centrally acting muscle relaxant, as a model drug. After intravenous administration of CZX, the decay of the plasma concentration was rapid and it was found that CZX obeyed one compartment open model in the dose range of 5 to 25 mg/kg. studied. The pharmacological response intensity was determined by means of the crossed extensor reflex. The duration of the muscle relaxant effect was proportional to the logarithm of the dose of CZX. The time course of the calculated plasma concentration was well related to the pharmacological response intensity via a Hill's equation and the simulated pharmacological response intensity which was obtained by means of the equation was coincident to the time course of the response data. These results indicated that the time course of pharmacological response intensity was able to be predicted using the time course of plasma concentrations. From the analysis of the quantitative relationship between the concentration and the effect under the present experimental conditions studied, it was found that the biophase compartment was identical to the central compartment as long as the first order processes were proceeding. These findings implied that the time course of pharmacological response would be quantitatively predictable from the disposition kinetics of CZX after the intravenous administration.

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The antinociceptive effects of lappaconitine (LA) and morphine (MOR) when injected intracerebroventriculary (i.c.v.), intracisternally (i.cist.) or intrathecally (i.t.) were investigated in mice by use of the tail pinch, hot plate and acetic acid-induced writhing tests. In addition, the effects of naloxone (NLX) administered subcutaneously on the antinociceptive action of LA and MOR were studied. LA and MOR after i.c.v., i.cist. and i.t. injection produced dose-dependent antinociception. MOR was more potent in the tail pinch and acetic acid-induced writhing tests by i.t. injection than by i.c.v. or i.cist. injection, but the potency in the hot plate test was independent of the injection site. On the other hand, like MOR, LA was more potent after i.t. injection than after i.c.v. or o.cist. injection in the tail pinch and acetic acid-induced writhing test. Its antinociceptive action was less potent than that of MOR. The antinociceptive actions of MOR were antagonized by NLX (1mg/kg.s.c.) in every test and injection site, whereas the antinociceptive actions of LA were not inhibited, except for the antinociception on the tail pinch test, which was partially antagonized by NLX. It is suggested that LA mainly produced an NLX-resistant antinociceptive effect at the spinal site.

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In polyadenylate directed polylysine synthesis, homologously cell-free extracts containing ribosomes and "s-100"(105, 000×g supernatant) from staphylococcal cells have less than one-half (one-tenth, when the extracts were stored at -80°C within a few weeks) of the activity of the extracts from Escherichia coli Q13. The present study of concerned with further improving the activity of staphylococcal ribosomes. The polylysine-synthesizing ability by staphylococcal ribosomes increased up to about two times as much as that by E.coli Q13 ribosomes, when "s-100" from E.coli Q13 was mixed with staphylococcal ribosomes which had been washed with a high salt HEPES buffer containing 10 mM HEPES, 1mM EGTA, 16mM magnesium acetate, 1.0M ammonium chloride and 0.1 mM dithiothreitol (pH7.6). Polylysine synthesis by the heterologous extracts has an advantage over polyuridylate-directed polyphenylalanine synthesis in the analysis of ribosome sensitivity for macrolide antibiotics, especially erythromycin.

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