Influence of subchronic treatment with haloperidol (0.5 to 5.0 mg/kg for 10 days, twice a day) on sensitivity of both central dopaminergic (DA) and muscarinic cholinergic (ACH) receptors was behaviorally and neurochemically investigated 4 days after withdrawal stage of the drug in the developing rat aged 28 days. An i.p. injection of apomorphine 0.2 mg/kg induced locomotor stimulation more effectively in haloperidol-treated animals than in controls. Scatchard analysis of the specific [³H] spiperone binding to the striatal membranes showed that haloperidol treatment produced an increase in the maximal number of binding sites (B_max) without alteration in a dissociation constant (K_D). Pilocarpine (100 and 150 mg/kg) was less effective in inducing catalepsy in the treated animals than in controls, although the treatment did not induce any alteration in saturation parameters of specific [³H] quinuclidinyl benzilate ([³H]QNB) binding to the homogenates of striatum, mesolimbic area and hippocampus. It is suggested that a decrease in B_max in the striatal [³H] spiperone binding by chronic haloperidol treatment underlies DA receptor hypersensitivity in developing rats. Behavioral muscarinic hyposensitivity caused by chronic haloperidol may not to be due to alteration in the striatal [³H] QNB binding.

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The first-pass metabolism of salicylamide (SAM) was studied in rabbits and rats paying main attention to the amounts of the glucuronide (SAMG) and sulfate (SAMS) formed. The roles of the intestine and liver for SAMG and SAMS formation during the first-pass were also examined quantitatively. Further, an equation was developed to estimate the hepatic firstpass metabolism based on the experiments of intravenous and oral administration and intestinal perfusion experiment. Significant species differences were found in these two animals. The extent of the first-pass metabolism was larger in rabbits (ca.95%) than in rats (ca.60%). Of the 95% first-pass metabolism in rabbits, about 30% is due to the intestine whereas the remaining 65% is due to the liver. Of the 60% in rats, about 20 and 40% are estimated to be due to the intestinal and hepatic first-pass metabolism, respectively. In rabbits, SAMG and SAMS are formed together in nearly equal amounts in the liver and at the ratio 4 : 1 in the intestine. In rats, on the other hand, SAMG is exclusively formed in the intestine and SAMS in the liver. In this context, the equation described here was applied to the data of Gugler et al. (J. Pharmacol. Exp. Ther., 195, 416-423 (1975)) who carried out a study on the first-pass metabolism of SAM in dogs, and consequently, reported that glucuronidation occurs primarily in the liver whereas sulfation occurs primarily in the intestine in dogs.

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The electron transfer mechanism in the reduction of aromatic nitro compounds by xanthine oxidase was investigated using methyl p-nitrobenzoate and p-nitroacetophenone as substrates. Methyl p-nitrobenzoate was reduced by both one-electron and more than twoelectron transfer mechanisms in the enzyme-electron donor system. When NADH was used as an electron donor, the ratio of one-electron flux to the total electron flux (the summation of one-electron and more than two-electron fluxes) was dependent on pH of the medium, but not on the concentration of the nitro compounds. The reverse was the case when the electron donor was xanthine. Additional experiments showed that methyl p-nitrobenzoate or p-nitroacetophenone was reduced to the corresponding hydroxylamino compounds and amino compounds by xanthine oxidase supplemented with xanthine or NADH. In these cases, the pattern of formation of the reduction products was dependent on the enzyme activity. The present study strongly suggested that the reduction of aromatic nitro compounds by xanthine oxidase proceeds through the four-electron and six-electron transfer mechanisms as well as the one-electron transfer mechanism.

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In order to measure Ca²⁺ efflux from the smooth muscle into a Ca²⁺-free physiological solution, the method using a Radiometer Ca²⁺-sensitive electrode was applied and compared with the method using an atomic absorption spectrophotometer to examine its usefulness. The results obtained show that the Ca²⁺ electrode used here can accurately and continuously monitor free calcium ions effluxed from the smooth muscle into a Ca²⁺-free solution. The Ca²⁺-sensitive electrode used here is a useful tool to investigate Ca²⁺ efflux from the smooth muscle into a Ca²⁺-free physiological solution.

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Cationic phenothiazine derivatives, anionic anthranilic acid derivatives and fluorescent probe 1-anilino-8-naphthalene sulfonate (ANS) which had hemolytic activities were used to investigate hemolysis of human erythrocyte. The observed hemolytic activities of drugs could divided into two categories : (1) the difference of the binding activity of drugs to the erythrocyte and (2) the difference of the membrane perturbation activity of drugs bound to the erythrocyte. The human erythrocyte had two kinds of binding sites for any drug used. The first site of them was already saturated before hemolysis occurred and the second site of them may play an important role in hemolysis by these drugs.

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The gas chromatographic assay method for pentaerythritol tetranicotinate, a nicotinic acid prodrug, and its hydrolysates was developed. The behavior of the drug in gastrointestinal tract was investigated in rat by using the method. The disappearance and hydrolysis of the drug were not observed in the gastric loop until 30 min. The rate of disapperance from the intestinal loop was 36.7% at 30 min which was significantly smaller than that of nicotinic acid. Little hydrolysis of the drug was observed in the buffer solution, pH 7.4, at 37° up to 2 hr. However, the consecutive hydrolysis was observed when the drug was incubated with everted intestine or plasma. As to the rate of hydrolysis of the drug and its esterform hydrolysates by scraped intestinal mucosa, the ester to which the larger number of nicotinic acid was bound was hydrolyzed more rapidly. These results indicate that the orally administered drug is enzymatically hydrolyzed in the intestinal mucosa by a consecutive reaction. Although the hydrolysis rate of pentaerythritol tetraicotinate is rapid, the rate of its ester-form hydrolysate becomes slower gradually as the nicotinic acid is released. The released nicotinic acid is rapidly absorbed. The behavior of the drug revealed in this study suggests that pentaerythritol tetranicotinate is useful as a prodrug of nicotinic acid.

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The mean hepatic extraction ratio ((ER)^^^-) of propranolo depending on the inflowing blood concentration to the liver was estimated directly by simultaneous measurements of arterial, hepatoportal, and hepatic venous blood concentrations of the drug following intravenous, intraportal, and intraduodenal administration in the rat. It was shown that the inflowing blood concentration to the liver caused considerable variation depending on the route of administration. The mean hepatic extraction ratio of propranolol in the first pass through the liver ((ER)^^^-)^f_<ipv> and that of the drug after escaping the hepatic first-pass metabolism ((ER)^^^-)^r_<ipv> were assessed by simultaneous administration of intraportal unlabelled propranolol and intravenous ¹⁴C-propranolol over a 50-min period. Consequently, a relation of ((ER)^^^-)^f_<ipv> ( (<ER)^^^-)_ipv ( (<ER)^^^-)^r_<ipv> was observed in higher propranolol doses, if ((ER)^^^-)_ipv refers to the overall mean hepatic extraction ratio following intraportal administration of propranolol. The fraction of orally administered dose reaching the systemic circulation for a drug exhibiting nonlinear hepatic first-pass metabolism was discussed. The unusual AUC-dose relationship of propranolol reported previously in the rat could be explained on the basis of both the nonlinear hepatic first-pass metabolism and the nonlinear hepatic metabolism of drug surviving the hepatic first-pass metabolism.

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β-Cyclodextrin (β-CyD) significantly protected the human erythrocytes from hemolysis and shape changes induced with chlorpromazine and flufenamic acid in isotonic solution. A good correlation between the stability constants of inclusion complexes (β->γ->α-CyD) and the inhibitory effects on drug-induced hemolysis was found. From the observations of drug uptake into erythrocytes and changes in surface tension, the protective effects of CyDs appeared to be due to the decrease in effective concentration of drug through inclusion complexation rather than the direct interaction of CyDs with erythrocyte membrane.

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Isoniazid (INH) was incubated with isolated rat hepatocytes, and the amounts of acetyl-INH, monoacetylhydrazine, diacetylhydrazine and hydrazine formed were determined by gas chromatography-mass spectrometry (GC-MS). Subsequent analyses of kinetic parameters of metabolic pathways and enzymological study of rat liver homogenate revealed that hydrazine was formed preferentially from INH, catalized by soluble hydrolytic enzymes.

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