Effects of diltiazem hydrochloride (DTZ) on digoxin (DX) concentrations in plasma and tissues (brain, heart, liver, and kidney) were studied in mice, and the effects were compared with those of quinidine sulfate (QD). When DX (0.2 mg/kg) was coadministered with DTZ (60 mg/kg) orally for 5 d to mice, plasma DX concentrations were increased significantly as with QD (100 mg/kg). Tissue DX concentrations were also increased in brain, heart, and liver. However, the DX tissue/plasma concentration (T/P) rations for brain, heart, and kidney were rather decreased with DTZ or QD. The increased plasma and tissue DX concentratios and the decreased T/P ratios with DTZ might be responsible for both the displacement of tissue DX binding and reduced DX elimination as with QD.

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We simultaneously determined the time course of the anti-exudative effects of three types of anti-inflammatory drug and their concentrations in serum and pleural exudate in carrageenin-induced pleurisy in rats. Dexamethasone (DM, steroidal anti-inflammatory drug, 0.1 mg/kg, p.o.) in spite of the gradual decline of DM concentration in the pleural exudate with time and its actual loss at 16 h after carrageenin, showed an anti-exudative effect throughout the period of testing after carrageenin which was more marked in the relatively late phase than in the relatively early phase. Mepirizole (MP, non-acidic, non-steroidal antiinflammatory drug, 100 mg/kg, p.o.) showed an anti-exudative effect only at 3 h after carrageenin and not thereafter, although MP concentration in exudate was the same between 3 and 6 h after carrageenin and then declined gradually. Ketoprofen (KP, acidic, non-steroidal anti-inflammatory drug, 1 mg/kg, p.o.) showed an anti-exudative effect for 6 h after carrageenin and not thereafter, while KP concentration in exudate reached the peak at 3 h after carrageenin and then declined with time. However, at the relatively late phase (10 h after carrageenin) the twice administration of KP resulted in an increase in its exudate concentration enough to show an anti-inflammatory effect, but did not result in any more anti-exudative effect than the single administration of KP. Therefore, these differences in the anti-exudative effects of three types of anti-inflammatory drug can not be explained by the change in their concentrations in the inflamed tissue, but may reflect the difference in their intrinsic anti-inflammatory activities. The anti-inflammatory drugs accumulated in the inflamed pleural cavity independently of their ability to bind to plasma proteins, because the ratio of concentrations of three types of drug in exudate to those in serum were similar in spite of marked differences in protein binding capacities among these drugs.

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Plasma levels of γ-butyrolactone-γ-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417), an analog of thyrotropin-releasing hormone, were determined by a radio-immunoassay after oral or intravenous administration in rats and dogs. A pharmacokinetic analysis after intravenous injection revealed biphasic elimination of the plasma concentration following a two compartment open model with half lives in α-phase of 2.0 min and β-phase of 19.2 min in rats, and half lives in a-phase of 4.0 min and β-phase of 33.0 min in dogs. Absolute bioavailabilities when administered orally the solution of DN-1417 after 24 h fasting in rats and dogs were 1 and 10%, respectively. The bioavailability was observed to be unchanged at the dose up to 500 mg/kg in rats and at the dose up to 100 mg/dog in dogs. Thus, the absorption of DN-1417 in rats and dogs was proportional to the dose. On the other hand, the absolute bioavailabilities after meal in dogs were 7.9% at the dose of 20 mg/dog and 7.2% at the dose of 2 mg/dog, whereas in the 24 h fasting condition they were 15.7 and 12.0%, respectively, showing the decrease in absorption with food ingestion. These phenomena are somewhat different from the absorption of thyrotropin-releasing hormone.

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The effect of acute renal failure (ARF) on the pharmacokinetics of propranolol was investigated. The model of ARF was produced by the subcutaneous injection of uranyl nitrate to rats (10 mg/kg) and was used 3 d after treatment. Uranyl nitrate-treated rats showed significantly higher plasma concentrations of propranolol after oral administration and the area under the plasma concentration-time curve increased about 3-fold compared to control rats. The plasma disappearance of propranolol after intravenous administration did not differ significanly between control and ARF. The mean availability of propranolol after oral administration increased from 0.120 in control to 0.215 in ARF (p<0.005). Absorption of propranolol was almost complete and no significant difference was found between two groups. No changes in plasma protein binding of propranolol and hepatic blood flow were observed in ARF. On the other hand, hepatic clearance of propranolol determined by liver perfusion studies showed a significant reduction in ARF and the calculated intrinsic clearance of unbound propranolol at a dose of 6.25 mg was 26.8±2.3 ml/min in control and 16.0±2.3 ml/min in ARF (p<0.01). These results demonstrate that the oral availability of propranolol increased in ARF due to a reduction in the hepatic presystemic elimination as compared to healthy control rats.

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A novel method was proposed to predict the elimination half-lives of cephalosporins from plasma protein binding (unbound fraction, f) and fraction of the dose excreted into urine (f^*) on the basis of the following four assumptions. 1) The drug is only distributed to the extracellular fluid, 2) the bound fraction of the drug in plasma is independent of the plasma drug concentration, 3) the binding protein of the drug is albumin, 4) the unbound drug in plasma is excreted by the glomerular filtration and the contribution of active secretion andreabsorption is negligible. The V_ss's and t_1/2β's of MT-141, one of cephalosporins, in rabbits, dogs and healthy human subjects were well predicted, whereas in rats, the prediction of the both values was failed The t_1/2β's of various cephalosporins in healthy subjects were calculated from f and f^*, in reasonably good agreement with the observed ones, except for some cephalosporins which have been reported to be secreted actively in the renal tubules. Thus, the comparison of the calculated t_1/2β's with the observed ones makes it possible to presume the renal excretion mechanism. Moreover, this method will be applicable to other drugs which satisfy the above four assumptions.

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The tissue distribution and the urinary excretion of hydrazines, hydrazine, acetylhydrazine and 1, 2-diacetylhydrazine, were determined by mass fragmentography using a gas chromatography-mass spectrometer equipped with a multiple ion detector-peak matcher. Using the compounds labeled with a stable isotope as an intemal standard, namely the isotope dilution method, made it possible to estimate trace amounts of hydrazine and its metabolites in the tissues. Significantly high levels of all hydrazines were detected in the kidney. Especially, acetylhydrazine, a metabolite of hydrazine, accumulated to a great extent in the kidney. Free hydrazine which was liberated from acetylhydrazine was detected both in the tissues and in the urine after the administration of acetylhydrazine. This demonstrates clearly that the metabolic pathway between hydrazine and acetylhydrazine is reversible.

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Reactivities of biologically active compounds with superoxide radicals were examined by measurement of electron spin resonance (ESR) spectra of 5-hydroperoxy-2, 2-dimethy 1-1-pyrrolidinyloxyl formed from 5, 5-dimethyl-1-pyrroline-1-oxide and the superoxide radicals generated by xanthine-xanthine oxidase system. Quantitative determination of the superoxide rachcals was performed by comparing the intensity of the spin adducts with chat of 4-hydroxy-2, 2, 6, 6-tetramethyl-pipperi-dinooxyl whose spin concentration was determined. Methyl viologen enhanced the formation of this spin adducts, while, rutin and luteoskyrin prevented it.

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cis-trans Isomerization of 3-(5-nitro-2-furyl)-2-(2-furyl)-acrylamide(AF-2) using Escherichia coli B/r and its two 5-nitro-2-furaldehyde semicarbazone(nitrofurazone)-resistant mutants was investigated. The isomerizing activity was detected in all three strains and markedly increased with acquiring resistance to nitro-furazone in intact cells and cell free extracts. Two distinct isomerases, nicotinamide adenine dinucleotide phosphate(NADPH)-dependent one with high activity and NAD(P)H-dependent with low activity were separate by sephadex G-100 and Sepharose 4B columns. Both enzyme activities agreed with the nitrofurazone-reducing activity due to O₂-sensitive nitroreductase as reported previously. Another nitroreductase, 0₂-insensitive one, was unable to isomerize cis AF-2 to trans form. These results suggest that bacterial cis-trans isomerases are not O₂-insensitive nitroreductase, but O₂-sensitive ones.

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A phosphorus-free lipid with a transient antihypertensive effect was found in a dog peritoneal dialysate by a modified procedure. On silicic acid chromatography of the crude extract, a new hypotensive factor and a new hypertensive factor were separated besides the known antihypertensive phospholipid resembling lysolecithin (Peritoneal dialysate depressor-I). The new antihypertensive factor was purified almost completely by gel filtration on a Sephadex LH-20 column, and found to contain no phosphorus. It was tentatively named Peritoneal Dialysate Depressor-II. The main spot detected on preparative thin-layer chromatography by charring with ethanolic sulturic acid reagent was found to be responsible for the antihypertensive action. This factor caused a sharp decrease in systemic arterial blood pressure of rats, cats and guired pigs when injected into the femoral vein. There was no significant change in the heart rate during this hypotension. The hypotensive activity was not affected by previous treatment of the rats or guinea pigs with antimuscarinic, antihistaminic, β-adrenergic-blocking or ganglionic-blocking agents. The antihypertensive effect of the factor was unaffected on rats pretreated with yohimbine, indomethac in or theophylline. In spinal or reserpinized rats, no detectable reduction of the depressor activity was observed. The factor did not affect isolated guinea pig ileum. Its depressor activity was not changed significantly by its treatment with proteases. No prostaglandin E or F series compounds were detected in the preparation by fluorometric assay with 15-hydroxyprostanoate oxido-reductase and resazurin. The hypotensive factot caused no aggregation of cat or rabbit platelets. The activity was not due to any known antihypertensive agent, such as acetylcholine, histamine, substance P, bradykinin, prostaglandins, platelet activating factor, lysophosphatidic acid and other known depressor compounds, as shownby various chemical and pharmacological examinations. Thus, the new hypotensive factor seems to be a lable lipid containing no phosphorus.

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Epileptogenic activity induced by intravenous injection of certain cephalosporin derivatives was studied. Ceftezole provided the most potent epileptogenic activity among the drugs tested. Changes in seizure patterns on electroencephalogram (EEG) tracings and behavioral signs after administrations of cefotiam and cefazolin were similar to those seen after ceftezole, though the intensity and duration were less than those of ceftezole. Cephacetrile and cephaloridine elicited the spiking activity in the frontal cortex and the other regions without apparent behavioral changes. Latamoxef and cefmenoxime displayed a weak epileptogenic activity at a dose of 1000 mg/kg. On the other hand, cephapirin, cefmetazole and cefoxitin did not evoke any changes in EEG nor in behavior. Penicillin G at a dose of 200 mg/kg affected spike or spike-and-wave complex in a few cases, but at a dose of 500 mg/kg the animals died of dyspnea almost immediately after injection without showing apparent epileptogenic signs. These results suggest that some of cephalosporins such as ceftezole, cefotiam, cephacetrile and cefazolin provide epileptogenic activity at higher doses.

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For the development of therapeutic agents that are coupled to tumor specific cariers, an artificial protein hybrid conjugate (immunotoxin) containing monoclonal anticarcinoembryonic antigen (CEA) antibody which binds specifically to the cell surface of CEA-producing tumor cells and a toxic subunit of ricin (A-chain) was prepared. This conjugate exerted strong cytotoxicity specifically toward CEA-producing tumor cells in vitro. In vivo, it has anti-tumor effects on ascitic tumor cells, and on free tumor cells before the solid tumor has been established. However, for the established solid tumor, a significant decrease of tumor growth was not seen even after repeated intravenous administrations of the antibody-ricin A-chain conjugate. Furthermore, the conjugate was found to be stable in both mouse and human serum in vitro, but after intravenous injection, it was inactivated in vivo quickly.

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A laminar flow absorption model for a carrier-mediated transport was developed to analyze the data of the intestinal single perfusion experiment. By using this model, we calculated the absorption rate and the concentration of the substance (drug) at the aqueous-intestinal membrane interface (c_wall). The absorption rate was smaller than that predicted by the Michaelis Menten equation, using the concentration at the inlet (c₀). The apparent Michaelis constant (K_{m, app}) was larger than the true Michaelis constant (K_m), if the data were analyzed by using the simulation curve of the absorption rate vs. c₀ as the usual method. This is because c_wall was smaller than c₀. But the maximal transport velocity (V_max) was little affected, because C_wall became almost equal to c₀ when c₀ was high. By using this model, we can determine the values of V_max and K_m which are not biased by the unstirred water layer in the intestinal tract.

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