A Simple and convenient numerical integration method was developed for the purpose of analyzing the pharmacokinetics of phenytoin not only at steady state but also at non-steady state. The algorithm was linked on a nonlinear least-squares method program MULTI2 (BAYES). The computing time was significantly decreased compared to Runge-Kutta-Gill Method at analysis by the Simplex algorithm and calculating precision was higher, especially at a large integration interval. This method was found to be sufficiently applicable to the analyses of the serum concentrations of phenytoin at nonsteady state as well as at steady state and the dosage adjustment by simulation. The flexibility of analyzed parameters on a microcomputer can be overcome by analyzing at the integration subinterval smaller than 0.25 h with the appropriate initial values of parameters, although very time consuming, or by using the Bayesian method with appropriate population parameters.

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Influence of long term SO₂ exposure on the pulmonary surfactant in rats was studied by means of chemical analysis and microscopic verification. At a time after termination of the exposure period, the general symptom in rats was similar to that of bronchitis. The content of disaturated phosphatidylcholine, a main functional component of the pulmonary surfactant, significantly increased not only in broncho-alveolar lavage fluid but also in pulmonary microsomal fraction by long term SO₂ exposure. Microscopic verification of alveolar type II cells from the bronchitic rats demonstrated the development of rough surface endoplasmic reticulums and an increase of the number of osmiophillic bodies. The results suggest that pulmonary surfactant production and/or secretion are activated in rats with bronchitis caused by long term SO₂ exposure.

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The stereoselective reduction of acetohexamide, an oral antidiabetic drug, was studied by using the cytosol of rabbit liver. A major metabolite of acetohexamide was isolated in 41.5% yield from the enzyme reaction mixture, and identified as (-)-hydroxyhexamide by techniques including the melting point, thin-layer chromatography, infrared spectrometry and optical rotation. The enantiomeric purity of (-)-hydroxyhexamide was determined on the basis of the proton nuclear magnetic resonance (400 MHz) spectrum of ester (diastereomer) derived by the reaction of (-)-hydroxyhexamide with (R)-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride. The (-)-hydroxyhexamide isolated from the enzyme reaction mixture was almost 100% in that enantiomeric form. The metabolic reduction of acetohexamide in the cytosol of rabbit liver appeared to be catalyzed by some enzymes with the same stereoselectivity.

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The relationship between the inhibition of the degradation of human calcitonin (HCT) in the supernatant of the rat's oral mucosa homogenate and the promoting effect on the rat's oral mucosal absorption of HCT was investigated by using ten kinds of sodium bile salts. The promoting effects and the inhibition of the degradation by the dihydroxy bile salts were related to the hydrophobicity, respectively. The inhibition of the degradation of HCT was related to the promoting effect on the oral mucosal absorption of HCT in the presense of the dihydroxy bile salts and to the concentration of the bile salts. Furthermore, the micelle formed by the bile salts would be concerned with the inhibition of the degradation of HCT.

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Hydrolysis of ursodeoxycholyl-p-aminobenzoic acid (PABA-UDCA), a synthetic bile acid conjugate used for the evaluation of the activity of intestinal bacterial growth, was studied with pancreatic enzymes, carboxypeptidase A, carboxypeptidase B, trypsin α-chymotrypsin, cholylglycine hydrolase, liver homogenate, small intestinal homogenates, and plasma, in comparison with the hydrolysis of glycocholic acid, ursodeoxycholyl-L-leucine (L-Leu-UDCA), and ursodeoxycholyl-L-lysine (L-Lys-UDCA). PABA-UDCA was specifically cleaved by bacterial cholylglycine hydrolase to ursodeoxycholic acid and para-aminobenzoic acid (PABA), but not by pancreatic enzymes. L-Leu-UDCA was cleaved by pancreatic enzymes, carboxypeptidase A, and cholylglycine hydrolase. L-Lys-UDCA was cleaved by pancreatic enzymes, carboxypeptidase B, and cholylglycine hydrolase. The small amount of glycocholic acid was cleaved by pancreatic enzymes and carboxypeptidase A and B, and cholylglycine hydrolase hydrolyzed glycocholic acid completely. In everted gut sac experiments, PABA-UDCA was absorbed by active transport in the rat terminal ileum, and the same rate of PABA was absorbed by passive diffusion in the four segments of the rat small intestine. These observations indicate that PABA-UDCA test can evaluate the activity of small intestinal bacterial growth.

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The effect of medium-chain triglycerides (MCTG) in lecithin-dispersed d-α-tocopherol acetate (VEA) preparation on intestinal absorption of VEA was investigated in rats using the in situ loop experiment. When VEA preparations containing soybean phosphatidylcholine (PC) and various amounts of MCTG were administered, the amount of VEA absorbed in 2 h was not significantly different among them. However, the amounts of total VE, sum of VEA and d-α-tocopherol (VE), remaining in the luminal fluid and the intestinal tissue were dependent on the MCTG content. Total VE remaining in the intestinal tissue after the administration of a VEA/PC/MCTG (5/16/1 by weight) preparation was nearly twice of VEA/PC (5/16) preparation, although the effect of MCTG varied with the increase or decrease in the MCTG content. Moreover, the increased tissue accumulation of total VE by the VEA/PC/MCTG (5/16/1) preparation resulted in an increase in the plasma VE concentration after the removal of the luminal fluid. No effect of pretreatment with PC/MCTG (1/1) dispersion on the tissue accumulation of total VE from VEA/PC (5/16) preparation was observed. Furthermore, the plasma concentration of VE from VEA and/or VE taken up in the tissue from the VEA/PC preparation was not increased by the treatment with the PC/MCTG dispersion. These results suggest that MCTG should coexist in the luminal VEA preparation to enhance the mucosal uptake. A similar enhancing effect was also observed by the addition of the metabolite of MCTG, a medium-chain fatty acid. When caprylic acid was added to the VEA/PC preparation, the tissue accumulation of total VE was also increased in comparison with the VEA/PC preparation, and the increased amount was not significantly different from VEA/PC/MCTG (5/16/1) preparation.

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Changes of the fluorescence spectra and quantum yield of pyrene-1-butyric acid (PYB) induced by rat (RSA), horse (HoSA), and pig serum albumins (PSA) and rat serum were compared at pH 7.4. RSA and rat serum caused marked quenching of the PYB fluorescence. On the contrary, HoSA and PSA increased the fluorescence intensity. In RSA and rat serum solutions, the PYB fluorescence intensity due to monomer emission was greatly diminished, and an additional emission due to excimer formation appeared at 480 nm. On the other hand, in the case of HoSA and PSA solutions, monomer emission gave rise to high fluorescence intensity and no excimer formation was observed. The binding parameters of PYB to RSA, HoSA, and PSA as well as human (HSA), bovine (BSA), rabbit (RbSA) and dog serum albumins (DSA) were compared by equilibrium dialysis method. The primary binding site affinity was in the order RSA>HSA>HoSA>RbSA>DSA≥BSA>PSA. However, for RSA and HSA, which showed reduced monomer emission and clear excimer fluorescence, the primary binding site number (n₁) was 2.71 and 2.90, respectively, considerably greater than those values for the other serum albumins. These findings suggest that PYB binds to RSA and HSA as a dimer. On the other hand, PYB appears to bind with BSA, RbSA, DSA and HoSA as a monomer. The primary binding site was not clearly recognized in PSA, which showed little enhancement of fluorescence. The similar behavior of RSA and HSA in the PYB binding may be attributed to their resemblance in the hydrophobic environment and flexibility around their binding sites.

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The effects of indeloxazine and piracetam, which reportedly prevent experimental impairments of memory and learning, on long-term potentiation (LTP) of the population spike in the mossy fiber-CA3 system were studied in vitro using the guinea pig hippocampal slices. Indeloxazine (10^-6 M) or piracetam (10^-4 M) significantly augmented the LTP and the effect of indeloxazine on the LTP was approximately 100 times as potent as that of piracetam.

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The in vitro effect of phenobarbital on glutathione S-transferase (GST) activity toward 1-chloro-2, 4-dinitrobenzene (CDNB) in rat hepatocyte culture was investigated. Treatment of hepatocytes with a medium containing 6 or 8 mM phenobarbital for 20 h increased the specific activity of GST approx. 140% and 160% of control, respectively. When induction of GST by phenobarbital treatment was observed, the cellular level of phenobarbital determined by HPLC was approx. 10-15 μg/mg of 20000×g supernatant protein of hepatocytes. Thus, an inductive effect of phenobarbital on GST was observed in vitro as well as in rat liver. It was suggested that a certain level of cellular phenobarbital was necessary for the induction.

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Fura 2-loaded thoracic aorta strips from rabbits were used. Norepinephrine and clonidine induced an increase in cytosolic Ca²⁺ concentration ([Ca²⁺]_i) and in muscle tension in a concentration-dependent manner. A positive correlation between ([Ca²⁺]_i) and tension development due to norepinephrine and clonidine was noted in muscle strips both untreated and treated with phenoxybenzamine (PBZ). As the total receptor population was reduced by the PBZ treatment, norepinephrine acted as a partial agonist in the treated strips. The slope of a regression line for norepinephrine in the untreated muscle strips was significantly smaller than the slopes for the same drug in PBZ-treated strips and for clonidine, suggesting that norepinephrine in the PBZ-treated strips and clonidine induced a greater tension at same [Ca²⁺]₁ than did norepinephrine in the untreated strips.

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