To investigate possible mechanisms for the long-lasting pharmacokinetic properties of cefpiramide, pharmacokinetic and renal clearance studies were carried out using rabbits. Cefazolin was employed as a reference compound. In pharmacokinetic studies, the plasma half-life (t_1/(2β)) for cefpiramide was 2.7 times as long as that for cefazolin. The total body clearance (Cl_T) and renal clearance (Cl_R) for cefazolin were approximately 2.3 times larger than those for cefpiramide. In renal clearance studies, the clearance by glomerular filtration (Cl_f) for cefpiramide exceeded Cl_f for cefazolin by 2.5 times, because of lower plasma protein binding of cefpiramide. In contrast, the clearance by tubular secretion (Cl_s) for cefpiramide was one-fifth as small as Cl_s for cefazolin. The overall renal clearance (Cl_r) for cefazolin was 3.6 times as large as Cl_r for cefpiramide, being in good agreement with the cefazolin/cefpiramide ratios of Cl_T and Cl_R. Therefore, the long-lasting pharmacokinetic properties of cefpiramide was suggested to be due to the fact that cefpiramide undergoes renal tubular secretion to less extent.

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Effects of antiallergic agents on 2, 4-dinitrophenylated Ascaris extract (DNP-As)-induced bronchial asthma were studied in Lewis rats, and compared with those on passive cutaneous anaphylaxis (PCA). Effects of methysergide and chlorpheniramine on the bronchial asthma model were also investigated. Rats were actively sensitized with DNP-As antigen and with killed Bordetella pertussis. After 8 d, asthmatic response was provoked by inhalation of DNP-As. The bronchomotor response was measured with a modified Konzett-Rossler method in diaphragm-sectioned rats. The inhalation of DNP-As caused a marked asthmatic bronchoconstriction without significant effect on systemic blood pressure and heart rate. Disodium cromoglycate (DSCG), 10 mg/kg, i.v., trans-4-guanidinomethylcyclohexanecarboxylic acid p-tert-butylphenyl ester hydrochloride (NCO-650) and tranilast at doses of 30 and 100 mg/kg, intraduodenally, significantly inhibited the asthmatic response. Chlorpheniramine and methysergide at a dose of 1 mg/kg, i.v. also significantly inhibited it. The above doses of NCO-650 and tranilast significantly inhibited 48 h PCA, while DSCG almost abolished the PCA. These results indicate that 1) NCO-650 and tranilast inhibited both the asthmatic response and PCA in almost the same degree, 2) DSCG inhibited PCA much more strongly than asthmatic response, and 3) histamine and 5-hydroxytryptamine may be involved in this asthmatic response.

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A bsorption site and some biological and pharmaceutical factors affecting the absorption and transport of ciclosporin A (CiA) from the gastrointestinal (GI) tract into both the thoracic lymphatics and the systemic circulation have been studied in rats. In a group of rats whose gastric emptying of orally administered CiA in HCO-60 formulation, 7.0 mg/kg, was physically prevented, both the lymphatic and the systemic availabilities of CiA were negligibly low. CiA was orally administered to another group of rats whose major intestinal lymphatics as well as thoracic lymph ducts were cannulated, and it was revealed that the amount of CiA delivered to the major intestinal lymphatics was about six times greater than that of CiA transferred into the thoracic lymphatics. In bile fistulous rats, the systemic availability of CiA was predominantly decreased but the lymphatic availability was not so decreased. In contrast, solvents such as propylene glycol and polyethylene glycol affected both the systemic and the lymphatic availabilities of CiA, which were also dependent on the absorption site. In particular, the lower small intestine does not contribute to the lymphatic availability of CiA.

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The influence of N, N-diethyl-m-toluamide (Deet) and 1-dodecylazacycloheptan-2-one (Azone), on skin permeability was examined for nifedipine (NP), taking into account their effects on the thermodynamic activity of the drug. The percutaneous absorption efficiency of NP was determined by measuring the drug concentration in rat plasma. Comparisons were made among NP suspensions in the enhancers to ensure equal thermodynamic activity. Azone increased NP penetration over that of propylene glycol (PG), while Deet produced a similar response to that of PG. The addition of a small amount of Deet to PG or diethyl sebacate (DES) provided for a rather large increase in NP penetration compared with that from PG or DES alone. The results of this study strongly suggest that Deet and Azone have different modes of action. Azone exerted a genuine effect on the skin and produced marked improvement in the penetration of NP. The effect of Deet was interesting as it was effective only in combination with other vehicles. Deet exhibits excellent solubilizing properties and penetrates the skin easily. Accordingly, it may be concluded that Deet functions simply as a cosolvent to produce saturated or supersaturated solutions of the active ingredient by its rapid disappearance from the vehicle, and thereby maximizes the thermodynamic activity of the drug.

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In order to clarify the effect of piretanide in the nephrons, pharmacokinetics and pharmacodynamics of piretanide were studied under a hydropenic condition in the rabbit. The hydropenic condition was developed by a simultaneous infusion of an antidiuretic hormone and hyperosmotic saline. Lithium was used as the indicator of the proximal sodium reabsorption. Plasma concentrations and urinary excretion rates of piretanide were not influenced by the hydration state of the body. The glomerular filtration rate (GFR) showed a long lasting decrease after piretanide administration; however, the urinary excretion rates of salts and water were increased prominently just after administration. The lithium clearance ratio, which was obtained by dividing the lithium renal clearance by GFR, indicated that piretanide inhibited the proximal reabsorption of sodium. The urine osmolarity after piretanide administration showed a significant decrease, and this indicated that the osmolarity of the renal medulla was also influenced by piretanide. From these observations, a model describing the transport of water and osmotic substances in the nephrons was constructed to calculate the effect of piretanide. The results indicated that the diuretic effect of piretanide in the hydropenic rabbit was reasonably described by the model. The model parameters obtained suggested that the site of action of piretanide in the proximal tubules might be in the peritubular side rather than inside the lumen, whereas the site of action in the loop of Henle might be inside the lumen.

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The inhibitory effects of ketoconazole (KCZ) and miconazole (MCZ), imidazole containing antimycotics, on the hydroxylations of testosterone as a model for endogenous steroids, and the N-demethylation of aminopyrine and the hydroxylation of aniline as models for xenobiotics were compared with those of cimetidine in mouse hepatic microsomes. In vitro, both KCZ and MCZ inhibited these enzyme activities in a dose-dependent manner. The inhibitory potencies of KCZ and MCZ for testosterone hydroxylations and aminopyrine N-demethylation were much greater, with 50% inhibition concentration (IC₅₀) values 2-3 orders of magnitude lower than those of cimetidine, while the potencies of these antimycotics for aniline hydroxylation were similar to that of cimetidine. Although KCZ, MCZ and cimetidine produced type II difference spectra, the difference between the antimycotics (405 nm) and cimetidine (392-405 nm) was found in the trough position of the difference spectra. Spectral dissociation constants (K_s) of these antimycotics (2.2×10^-7-5.4×10^-6M) were also 1-2 orders of magnitude lower than those of cimetidine (1.3×10^-5-1.6×10^-4M), and both KCZ and cimetidine had two kinds of K_s, while MCZ had a single K_s. Pentobarbital sleeping time was prolonged in a dose-dependent manner by the i.p. administration of 10-50 mg/kg of KCZ, MCZ or cimetidine, and the potencies for the prolongation of sleeping time decreased in the order of MCZ>KCZ>cimetidine. These results indicated that the inhibitory potencies of KCZ and MCZ for the cytochrome P-450-mediated oxidative metabolism of testosterone and xenobiotics in hepatic microsomes were greater than those of cimetidine, and that the affinities of KCZ and MCZ for some cytochrome P-450 species in hepatic microsomes differed from one another.

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Corneal permeability of bunazosin, one of the alpha-adrenergic receptor antagonists, was investigated in vitro using excised rabbit cornea mounted on a corneal permeability apparatus, and the enhancing effects of various acids on the permeability of bunazosin were evaluated. Caprylic and capric acid elevated octanol/water partition coefficient of bunazosin, and corneal permeability was increased, probably as a result of ion-pair formation between them. Neither bunazosin, these acids, or the ion-pair caused corneal swelling. These acids, in contrast, had little effect on the partition of pilocarpine, or on corneal permeability.

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The intestinal absorption process of 1-O-[p-(myristyloxy)-α-methylcinnamoyl] glycerol (LK-903), a new hypolipidemic compound, was studied in rats. When ³H-LK-903 or ³H-LKA [³H-p-(myristyloxy)-α-methyl cinnamic acid], labeled at the cinnamic acid moiety, or ¹⁴C-LK-903, labeled at the glycerol moiety, were administered orally to thoracic duct-cannulated rats at a dose of 0.233 mmol/kg, 31.1, 6.7 and 18.1% of the dose, respectively, appeared in the lymph within 24 h. In this case, radioactive compounds in the lymph lipids consisted of LKA (radioactivity was not detected in the fraction of LKA with ¹⁴C-LK-903), LK-903, diglyceride analogues and triglyceride analogues. The percentages of the triglyceride analogues were the highest, followed by the diglyceride analogues. On the other hand, when doubly labeled LK-903 (³H/¹⁴C=1, corrected ratio) was administered orally, the values of ³H/¹⁴C for the monoglyceride, diglyceride and triglyceride analogues in the lymph were 1.2-1.5, 1.7-1.9 and 1.9-2.7, respectively. The lymphatic absorption of LK-903 was stimulated by the presence of lecithin but inhibited by a high dose of triolein. The results indicated that (1) LK-903 formed micelles in the intestine, (2) a large part of LK-903 was absorbed as such, (3) a part of LK-903 was hydrolyzed in the intestinal mucosa, and (4) a part of LKA formed by hydrolysis was again utilized to synthesize the higher glycerides and absorbed via the lymphatic absorption route for lipids.

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In the course of a modification study of iridoid glucosides to investigate their antitumor and antimicrobial activity, we found that about all metaperiodate oxidation products of iridoid glucosides which had no antitumor activity showed potent activity against the leukemia P388 in mice. They were found to be more active than the corresponding aglycones obtained by enzymic hydrolysis of iridoid glucosides. Among them, periodate oxidation product of sweroside showed the most potent activity, of which the maximum total/control (T/C) value was 198% at 200 mg/kg.

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A forced swimming test proposed by Porsolt is a useful method for screening antidepressants. To evaluate drug effects more objectively, vibration of the walls of a water tank caused by the escape behavior of the rat was recorded. Imipramine (IMI) increased the number of vibration and this effect was observed in the medial amygdala lesioned rat but not in the central or basolateral amygdala lesioned rat. The present result suggests that the medial amygdala is an important site of action of IMI.

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