The relationship between the membrane stabilizing action of β-adrenoceptor blockers and their physico-chemical properties was investigated. Their depressing effects on the action potential amplitude of isolated Rana sciatic nerve were examined. The orde of their depressing potencies was propranolol (PROP) > dichloroisoproterenol (DCI) > alprenolol (ALP) > methoxamine (MEX) > practolol (PRAC)=sotalol (SOTA). The order of the negative chronotropic potency on the isolated rabbit atrial rate was PROP > ALP > DCI > MEX > PRAC > SOTA. The order of β-blocking activity in isolated guinea-pig tracheal chain or in isolated rabbit atrial rate was ALP > PROP > SOTA > DCI > MEX > PRAC or PROP > ALP > PRAC > DCI > SOTA > MEX respectively. A high correlation was observed between membrane stabilizing actions (depressing effect on sciatic nerve action potential and negative chronotropic effect on atrial rate) and physico-chemical properties (the apparent partition coefficient and pK_b). No relation was observed between β-blocking effect on tracheal chain or right atrial rate and physico-chemical properties. It is suggested that the active sites for β-blocking action and membrane stabilizing action might be different.

抄録全体を表示

The pharmacokinetics of 4'-chloro-5-methoxy-3-biphenylylacetic acid (DKA-9) and its metabolites were studied in rats and humans. Appropriate equations describing models for rats and humans were fitted to the plasma (and urine) data using a non-linear least-squares analysis. 1. Rats : After intravenous administration (2.5 mg/kg) of ¹⁴C-DKA-9 to rats, the concentration of DKA-9 and 5-carboxymethyl-4'-chloro-3-biphenylyl hydrogen sulfate (DKA-24S) in plasma were both described by the two compartment model ; the half lives of hybrid rate constants [(t_1/2) α and (t_1/2) β] and the volume of the central compartment were 0.424, 2.91 hr and 0.101 L/kg for DKA-9, and 0.295, 8.07 hr and 0.129 L/kg for DKA-24S, respectively. Urinary excretion (% of dose) of radioactivity was 87.8±1.3% (mean±S.D., n=3) and 99% of which corresponded to DKA-24S. However, the concentration of 4'-chloro-5-hydroxy-3-biphenylylacetic acid (DKA-24), which is the precursor of DKA-24S, was found to be negligible in most of plasma, urinary, and fecal samples, therefore, this metabolite was neglected in the kinetic study. 2. Humans : When DKA-9 was administered orally to seven healthy male subjects, DKA-9 absorption and disposition did not virtually show a dose-dependency at doses of 42.8 and 85.5 mg : DKA-9 was absorbed from a gastro-intestinal tract with the half life [(t_1/2)_ka] of 0.525±0.129 hr (n=7) after the lag time (t_lag) of 0.526±0.266 hr ; the maximum concentration (C_max) of DKA-9 was 3.1±0.1 (n=3) and 5.5±0.4 μg/ml (n=4), and the area under the DKA-9 plasma concentration-time curve in 0-8 hr ([AUC]_0-8hr) was 6.85±0.54 and 13.1±0.9 μg·hr/ml after administration of 42.8 and 85.5 mg, respectively. Urinary excretion of DKA-9 and its metabolites (% of dose, n=4) were : DKA-9 (≒0), DKA-24 (≒0), 4'-chloro-5-methoxy-3-biphenylylacetyl β-D-glucopyranosiduronic acid (DKA-9G) (60.1±6.0%), 4'-chloro-5-hydroxy-3-biphenylylacetyl β-D-glucopyranosiduronic acid (DKA-24G) (8.1±0.4%), DKA-24S (13.9±0.4%), 5-carboxymethyl-4'-chloro-3-biphenylyl β-D-glucopyranosiduronic acid (DKA-24OG) (6.5±0.6%), and 2-(4'-chloro-5-methoxy-3-biphenylyl)-2-hydroxyacetic acid (αOH-DKA-9) (1.3±1.2%). Urinary excretion rate constants of DKA-9G and DKA-24G were found to be much greater in magnitude than those of DKA-24S and DKA-24OG, which suggests that acylglucuronides could be more easily excreted from plasma due to a lesser degree of plasma protein binding.

抄録全体を表示

Pharmacokinetics of soluble monocomponent insulin preparation was examined by using an in situ experimental model of rabbits. Rabbits were laparotomized under anesthesia, and prepancreatic duodenal vein, splenic vein, and hepatic artery were ligated, and cannulae were inserted into the hepatic vein, portal vein, abdominal aorta, and renal vein. After administration of the monocomponent insulin preparation, blood was drawn periodically from each cannula, exogenous insulin level was measured, and kinetic parameters were calculated from the blood level curves from the arteries. The parameters obtained were disappearance rate constant (K_el) of 0.128±0.013 hr^-1 and biological half-life (T_1/2) of 5.50±0.49 min. Rate of insulin uptake by each oragan was calculated from the difference in arterial and venous blood levels at each time period and values wee 12% for the liver and 31% for the kidney. No definite uptake was found in the digestive tract. Relationship between the potency of insulin and blood levels suggested that the minimum effective blood level of this insulin preparation was 20-30 μU/ml.

抄録全体を表示

"Inverse substrates" for bovine thrombin and human plasmin were demonstrated. "Inverse substrates" for the enzymes are characterized as specific substrates in which the arrangement of site-specific group is reversed compared to that of normal substrate, e.g., a cationic center is included in their leaving group instead of being in their acyl moiety (K. Tanizawa, Y. Kasaba, Y. Kanaoka, J. Am. Chem. Soc. 99, 4485-4488). Kinetic characteristics of thrombin, plasmin and trypsin toward "inverse substrates"were compared. Based on these observations, differences in active centers of the trypsin homologs were discussed. Behavior of p- and m-hydroxyphenylguanidine derivatives as new "inverse substrates" for trypsin was also reported.

抄録全体を表示

Controlling the duration of hypnotic effect of pentobarbital by simultaneously administered bemegride, the relationship between the duration of hypnosis and the degree of developed tolerance after acute or chronic treatment was investigated in mice. Bemegride attenuated the hypnotic effect of pentobarbital, but neither the brain level of pentobarbital nor the development of tolerance was modified by bemegride, indicating that the brain level of pentobarbital is the primary determinant for the production of tolerance and full duration of hypnosis is not essential in this mechanism.

抄録全体を表示