The pharmacodynamic behavior of orally administered chlorzoxazone (CZX) was studied in rats. From the time course of CZX plasma concentration data under alpha-chloralose (80 mg/kg, i. p.) anesthesia, it was found that CZX obeyed a one-compartment model with first-order absorption. The pharmacological response intensity of CZX on the crossed extensor reflex was closely related to the plasma concentration data via Hill's equation under alpha-chloralose (80 mg/kg) anesthesia, but not at a 150 mg/kg dose. The influence of alpha-chloralose at the latter dose on CZX pharmacokinetics and pharmacodynamics appeared to be due to the pharmacodynamic interaction of alpha-chloralose and CZX, thus suggesting that the pharmacokinetic and pharmacodynamic concept proposed by Smolen was not applicable to CZX's behavior at such a dose in rats. Under alphachloralose (80 mg/kg) anesthesia, the biophase compartment was determined to be identical to the central compartment using our proposed model. On the basis of the effect of anesthetics on drug behavior, one may select an appropriate anesthetic dose to evaluate the relationship between the plasma levels and the onset and duration of the drug action. At the higher dose of alpha-chloralose (150 mg/kg), the free fraction of CZX was increased and a possible enhancement in CZX action was suggested.

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Although effects of adrenergic agonists on metabolic activation of neutrophils have been studied for over a decade, amounts of released arachidonic acid and its metabolites from the cells activated by chemotactic peptide (FMLP) are so small that the results have been in conflict. In this study, we developed a method to obtain enough amount of arachidonic acid released to examine the action sites of adrenergic agonists with respects to the metabolic bursts of human neutrophils. First, superoxide generation from the cells was estimated and the results indicated that the adrenergic agonists, such as isoproterenol, salbutamol, procaterol and epinephrine, inhibited over 70% and 40% of the superoxide generation stimulated by FMLP and serum treated zymosan (STZ), respectively. Another metabolic activation, the release of arachidonic acid, was achieved by FMLP if the cells were incubated with merthiolate (20-80μM), but the merthiolate-treatment was ineffective on the cells activated by calcium ionophore (A23187). Isoproterenol and epinephrine decreased the arachidonic acid release only when the cells were activated by FMLP in the presence of merthiolate. In spite of the fact that isoproterenol (1 and 10 μM) hardly inhibited the arachidonic acid release activated by A23187, formations of leukotrienes were decreased up to approximately 70% of control level. Intracellular calcium concentration elevated by FMLP was hardly diminished by isoproterenol and salbutamol. From these observations, it appears likely that adrenergic agonists attenuate the signal transmission process of FMLP at a post-receptor site of action at a step before the activation of protein kinase C or phospholipase A₂.

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TI-31, at concentrations of 10 and 100μM, suppressed the antibody response to T celldependent (sheep red blood cells, SRBC) and -independent antigens (trinitrophenyl-lipopolysaccharide, TNP-LPS and TNP-Ficoll). The anti-SRBC response was suppressed by TI-31 when T cells were replaced by a supernatant of concanavalin A (Con A)-stimulated spleen cells, indicating the drug had influence on T lymphocytes, B lymphocytes and macrophages. TI-31 augmented the Con Ainduced suppressor T cell (Ts) assessed by anti-SRBC plaque-forming cells response in vitro. The drug (10mg/kg, p. o.) potentiated antigen specific Ts induction in vitro after injection of a high dose of SRBC. The results demonstrate that TI-31 enhanced Ts induction, which resulted in a diminution of antibody formation.

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The metabolites of 1-[bis (4-fluorophenyl) methyl]-4-(2, 3, 4-trimethoxybenzyl) piperazine dihydrochloride (KB-2796) in the bile, urine and feces in rats were investigated after oral administration of [methine-¹⁴C], [benzyl-¹⁴C] and unlabelled KB-2796. Their structures were characterized by thin-layer chromatography, mass spectrometry, proton nuclear magnetic resonance and comparison with synthesized authentic compounds. The main pathways of biotransformation of KB-2796 in rats were : (a) O-demethylation at each methoxy group of the trimethoxybenzyl moiety, (b) N-dealkylation at 1 and 4-position of the piperazine ring and (c) hydroxylation at 5-position of the 2, 3, 4-trimethoxyphenyl ring.

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The present study was designed to examine 1) the properties of [³H] ketanserin binding to serotonin-2 (5HT₂)-serotonergic receptors in the rabbit platelet membranes, 2) displacement affinities of various chemicals and 3) difference of the affinities between their chemicals and new agents, MCI-9042 and M-1. The plots of specific binding obtained from the Scatchard analysis using [³H] ketanserin for the platelet membranes were monophasic when the non-specific binding was determined by the use of 0.1 mM serotonin (5HT), and the K_d and B_max values were 3.93±0.41 nM and 1.19±0.20 pmol/mg protein, respectively. The displacement potencies of chemicals which were serotonin receptor-, dopamine receptor-, histamine receptor-, and α-adrenoceptor-related agents were characterized by [³H] ketanserin binding to 5HT₂-serotonergic receptor. The pK_i values of a new antiplatelet agent, MCI-9042, and its metabolite, M-1, were 7.19 and 7.59, respectively and these values were lower than those of ketanserin and pirenperone but higher than those of methysergide, cinanserin and cyproheptadine. The affinities of ketanserin for 5HT₂-receptors in the rabbit platelet were similar to those for 5HT₂-receptors previously identified in the rat frontal lobe and in canine aorta, but cinancerin was selective to 5HT₂-receptors in the rat frontal lobe and in canine aorta, prazosin was selective to 5HT₂-receptor in the rabbit platelet, and MCI-9042 and M-1 had the same affinities to the receptors in the rat frontal lobe and in the rabbit platelet. It is suggested that 1) the binding of [³H] ketanserin to 5HT₂-receptors in the rabbit platelet is dissociated by the new antiplatelet agents, MCI-9042 and M-1, 2) the affinities of some chemicals for 5HT₂-receptors in the rabbit platelet are not identical with those in the rat frontal lobe or in the canine aorta, and 3) [³H] ketanserin binding sites in platelets, neurons and/or blood vessels may consist of various subtypes.

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The effect of levocabastine on allergic and histamine (Hi)-induced conjunctivitis in guinea pigs was compared with those of cromolyn sodium and amlexanox. Levocabastine inhibited both antigen- and Hi-induced conjunctivitis. Amlexanox had no effect on Hi-induced conjunctivitis ; however, the drug elicited a significant inhibition of allergic conjunctivitis. On the other hand, the effect of cromolyn sodium was almost negligible in both cases. Levocabastine moderately inhibited Hi release from guinea pig conjunctiva induced by antigen-antibody reactions. Amlexanox also caused a significant inhibitory effect, whereas cromolyn sodium was not effective in suppressing Hi release induced by antigen challenge. Furthermore, levocabastine prevented an increase in the vascular permeability elicited by both Hi and antigen instillation.

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Transport mechanism of quinolonecarboxylic acid derivatives (quinolones), lomefloxacin and ofloxacin, in rat erythrocytes was investigated. The uptake of lomefloxacin by erythrocytes was apparently nonsaturable over the concentration range of 0.1-1.0 mM at 27°C and pH 7.4. In the case of ofloxacin, however, the erythrocytes took up ofloxacin in a concentration dependent manner at 20°C and pH 7.4, with a maximum rate (J_max) of 28.8±0.98 pmol/10⁶ cells/s and a Michaelis constant (K_t) of 0.92±0.15 mM. An increase in the medium osmolarity caused a decrease in the [¹⁴C] lomefloxacin uptake, indicating that the drug is transported into the intracellular space of erythrocytes. The uptake of [¹⁴C] lomefloxacin by the erythrocytes was independent of pH but increased above pH 6.0, and, moreover, was dependent on temperature with an activation energy of 16.6 kcal/mol. The uptake of [¹⁴C] lomefloxacin was competitively inhibited by a water-soluble vitamin, nicotinic acid, with an inhibition constant (K_i) of 16.1 mM, but not inhibited by 10 mM of L-alanine, glucose, p-aminohippuric acid (PAH), N-methyl-nicotinamide (NMN) or tetraethylammonium chloride (TEA). These lines of evidence suggest that the transport system of lomefloxacin and ofloxacin in rat erythrocytes is common with that of a water-soluble vitamin, nicotinic acid, to which quinolones are structurally analogous.

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The steady-state dialysis kinetics in buffer, erythrocyte suspension and muscle have been analyzed by clearance theory in the microdialysis study. "Tube"model has been demonstrated to be a useful model to relate the dialysis clearance, CL_D, the dialysis flow rate, F, and the permeability rate constant, PA, for microdialysis employing the transcranial type microdialysis probe. The effective dialysis coefficient (R_d), defined as the ratio of the in vivo PA and in vitro PA, was introduced to account for the differences between in vivo and in vitro microdialyses. The Arrhenius plot of the antipyrine permeability rate constant presented a single straight line in the range of 15-37°C with an activation energy of 5.49 kcal/mol. A fairly good correlation was observed between the reciprocal of the permeability rate constant and the root of the molecular weight in the range of 18-1039. On the contrary, the molecular weight and the plasma membrane permeability were not determinant factors for R_d value determined in the erythrocyte suspension (R_{d, erythrocyte}), while the interstitial fluid space (100-hematocrit)% of erythrocyte suspension plays a dominant factor to change R_{d, erythrocyte}. The in vivo permeability rate constant was determined in the muscle for [³H] water, [¹⁴C] urea, antipyrine and [¹⁴C] sucrose under the steady-state condition. No significant difference of R_d in muscle tissue was demonstrated for these four model substances. By using the R_d value, a hypothetical equation has been proposed to relate the concentration in the dialysate and the interstitial fluid at steady-state.

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