The purpose of this study was to clarify the reason why two similar perfluorochemical (PFC) emulsions, namely a mixed PFC (perfluorodecalin : FDC and perfluorotripropylamine : FTPA) and an FDC emulsion, resulted in a very different survival time for the exchange-transfused rats. Supposing that some difference in the intravascular behavior of both emulsions would account for such a difference in efficacy, experiments on behavior of PFC emulsions were carried out focusing on the particle size. It was reconfirmed that larger PFC particles were eliminated from the blood stream much more rapidly than smaller particles with three FMIQ (perfluoro-N-methyldecahydroisoquinoline) emulsions. After the FDC+FTPA emulsion or the FDC emulsion were injected into rabbits, PFC particles in the blood tended to decrease in size. When each of the collected blood samples was incubated at 37°C for 24 h, the FDC emulsion enlarged in size markedly, but the FDC+FTPA emulsion showed no change. The retention of PFC particles appeared to depend on the emulsion stability rather than simply on the emulsifying agent alone. These data showed that some differences were observed in intravascular persistence of the FDC+FTPA emulsion and the FDC emulsion, and suggested that the efficacy of PFC emulsions would reflect their behavior in the circulation.

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In the smooth muscle of the rat vas deferens, 10^-5M cocaine shifted the dose-response curve to norepinephrine to the left and enhanced the maximal contractions to norepinephrine and methacholine. Propranolol at 10^-4M almost completely blocked these potentiating effects of cocaine. Sotalol or lidocaine at 10^-4M did not block the potentiating action of cocaine. The cocaine-induced enhancement of the methacholine contraction and its blockade by propranolol was observed in the dibenaminetreated vas deferens. Propranolol also blocked the depolarization-induced enhancement of the methacholine contraction. Together with the previous study demonstrating the calcium-antagonist action for propranolol, these results suggest that propranolol blocks the cocaine-induced enhancement by inhibiting the calcium influx through the potential-dependent calcium channel in the rat vas deferens.

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To predict quantitatively drug interaction kinetics from the single-drug clearance studies, we examined the effect of iodopyracet (IOD) on sulfamethizole (SMZ) excretion in rabbits. Even though the decline of systemic IOD plasma concentration was linear, the renal clearance of SMZ decreased significantly in the presence of IOD. The results could be described by a perfusion model incorporated with the competitive inhibition for tubular secretion. For IOD with a high extraction ratio, it was suggested that a heavy load of the drug was supplied to the sites of secretion and caused the saturation of transport systems, even though the renal excretion kinetics were apparently linear in respect to the systemic circulation. These facts indicated that a linear relationship between the concentrations in the systemic circulation and at the sites of tubular secretion can not always be presumed. Consequently, SMZ-IOD interaction study stressed the importance of the drug concentrations at the sites of interaction for quantitative elucidation of drug-drug interactions.

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Pharmacokinetics of cefpiramide (CPM) were investigated in normal rats and rats with hepatic intoxication induced by a single oral administration of carbon tetrachloride (CCl₄). The elimination half-life of the antibiotic was prolonged in CCl₄-intoxicated rats and the total body clearance in CCl₄-intoxicated rats (153.9 ml/h/kg) was about 40% of the control value (390.3 ml/h/kg), while the volume of distribution for CPM was scarcely affected. The hepatic clearance of CPM was markedly diminished and the renal clearance of CPM was slightly, but not significantly, decreased in CCl₄-intoxicated rats. It seems that the hepatic clearance of CPM was decreased owing to at least two factors ; (1) decrease in CPM uptake by hepatocytes and (2) decrease in bile flow, while the renal clearance of CPM was slightly decreased owing to decrease in the renal tubular secretion. These results suggest that CCl₄ intoxicates not only the liver but also the kidney to a small extent.

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The effect of substance P (SP) on the antigen-induced bronchoconstriction in vitro and in vivo was investigated in guinea pigs. SP caused the contraction of isolated non-sensitized guinea pig tracheal muscle at concentrations between 10^-9 to 10^-7 g/ml. The elimination of epithelium in the tracheal muscle produced a slight enhancement of SP response as compared to control. Antigen-induced contraction of isolated sensitized guinea pig tracheal muscle was slightly enhanced by the pretreatment with SP at a concentration of 10^-9 g/ml. The SP-induced enhancement of antigen-induced contraction was siginificantly augmented by the elimination of epithelium of sensitized tracheal muscle. Moreover, the clear bronchoconstriction was observed by the infusion of SP (1μg/min) intravenously, but not by the infusion of SP at the rates between 0.1 and 0.01μg/min. Antigen-induced asthmatic respiratory disorder was accelerated temporarily by the infusion of subthreshold SP (0.1μg/min). The reactivity of bronchial smooth muscle measured by repeated injection of acetylcholine was significantly potentiated by the infusion of subthreshold SP (0.1μg/min). These results suggest that SP has dual actions in the contractile response of guinea pig airway smooth muscle. One is the direct contractile activity, and the other one is enhancing activity of antigen- and acetylcholine-induced bronchoconstriction.

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The enhancing effect of pyrrolidone derivatives on the percutaneous penetration of sulfaguanidine, aminopyrine and sudan III was investigated using in vitro technique and excised rat skin. 1-Methyl (MP), 1-hexyl (HP) and 1-lauryl-2-pyrrolidone (LP) were used as penetration enhancers. Aminopyrine showed high penetration through skin although sulfaguanidine and sudan III showed little penetration. Pyrrolidone derivatives enhanced their penetrations. Especially HP and LP enhanced the penetration of sulfaguanidine to a high extent. Sudan III was not detected in the receptor phase regardless of the presence of enhancer. Pyrrolidone derivatives significantly increased the skin accumulation of sulfaguanidine, aminopyrine and sudan III. Penetration of pyrrolidone derivatives was also determined. MP and HP showed high penetrations. LP was not detectable in the receptor phase. MP, HP and LP showed high skin accumulations. These results suggested the usefulness of pyrrolidone derivatives as percutaneous penetration enhancers.

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Interspecies variation in drug disposition can be considered to be a function of species body weight. Therefore, it is possible to establish allometric relationships between pharmacokinetic parameters and species body weight. Interspecies scaling of pharmacokinetic data yielded from laboratory animals can often provide reliable predictions of pharmacokinetic parameters and drug disposition in humans. Significant correlations between 3'-azido-3'-deoxythymidine (AZT) pharmacokinetic parameters (total clearance, renal clearance, nonrenal clearance and steady-state volume of distribution) from mice, rats, dogs, monkeys and humans and body weight were found. Plasma AZT concentration versus chronological time profiles were markedly different for each species. However, when chronological time was converted to pharmacokinetic (physiologic) time these profiles were superimposible. These results demonstrate that interspecies pharmacokinetic scaling can be used to estimate plasma AZT concentrations in humans and can be used to design initial dosage regimens.

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The transition state of acylation step of trypsin catalysis was determined by molecular orbital calculations. The calculations were carried out at the RHF-LCAO-SCF approximation level with double zeta basis set (plus polarization functions). The role of His57 residue in the acylation step of the catalytic reaction of trypsin was analysed from a quantum mechanical point of view. The influences of surrounding residues, such as oxyanion hole and Asp102^-, and the electrostatic effect of the other regions of the enzyme were also studied. His57 was proved to capture the proton from Ser195 side chain terminus with its lone pair and to transfer it to substrate with electrostatic assistance of Asp102^- and oxyanion hole.

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