The effect of oral administration of activated charcoal on the clearance of theophylline and phenobarbital following their intravenous administration was studied in rats. Oral administration of multiple doses of activated charcoal significantly decreased the serum half-life and AUC (area under the curve) and increased the total body clearance of both theophylline and phenobarbital as compared with their respective controls. The volume of distribution was not significantly different between treatments. A single dose of activated charcoal showed only a slight enhancement of clearance of theophylline. Accelerated clearance of both drugs by oral activated charcoal was rationalized in terms of adsorption of exsorbed drugs and inhibition of their reabsorption by activated charcoal in the gastrointestinal tract.

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The angiogenesis of adjuvant-induced pouch granuloma was studied in insulintreated diabetic mice by a newly established method using carmine dye. The 10% carmine suspension in 5% gelatin solution was infused through the tail vein of mice to be distributed to the end of the capillaries in the granulation tissue without leakage. The carmine dye was extracted from the tissue with 3 N NaOH solution and then measured by spectrophotometry. The content of carmine dye in the granuloma tissue in alloxan diabetic mice was observed to be significantly low during the first week after adjuvant injection when compared with normal mice, indicating poor development of blood vessels in the diabetic state. Diabetes-induced inhibition of the angiogenesis was completely restored by the treatment with insulin in a dose producing no hypoglycemic effect. These results were directly reflected by the formation of granuloma tissue. This method was established to be explicitly useful for measuring the angiogenesis, especially in mouse granuloma tissue.

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5-[(2-Aminoacetamide) methyl]-1-[p-chloro-2-(o-chlorobenzoyl) phenyl]-N, N-dimethyl-1H-s-triazole-3-carboxamide hydrochloride dihydrate (450191-S), a newly synthesized sleep inducer, is a masked compound which is converted to 1, 4-benzodiazepine by intestinal aminopeptidases during absorption from the small intestine. This study was an investigation on the effects of food on 450191-S pharmacokinetics. When ¹⁴C-450191-S was administered to non-fasted rats, peak plasma levels of total radioactivity were markedly reduced and its excretion into the bile was more delayed than when it was administered to fasted rats. One of the causes for these phenomena was thought to be a delayed absorption caused by the direct interaction between 450191-S and food in the intestinal lumen as well as the delayed gastric emptying rate. To confirm this interaction, we examined the effect of food on 450191-S uptake by the small intestine using rat everted jejunal sac in vitro. Subsequently, we found that the desglycylation of 450191-S was inhibited by rat food and that the uptake of 450191-S was reduced. In conclusion, 450191-S absorption is delayed by food, which results in the decreased total plasmal level of 450191-S metabolites.

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The amounts of mitomycin C (MMC) taken up into rat ascites hepatoma cells were determined by measuring the decrease in the absorbance of the incubation medium at 363 nm. The extracellular concentration of MMC decreased progressively in AH130 cell suspension and no peaks other than MMC were detected by analytical high-performance liquid chromatography (HPLC). Isoproterenol (IPN) enhanced the uptake of MMC into AH44 and AH130 cells but not AH13 cells in which the uptake increased by N⁶, O^2'-dibutyryl cyclic adenosine 3' : 5'-monophosphate (dibutyryl cyclic AMP). The increase of uptake of MMC by IPN was inhibited by propranolol and the uptake of MMC increased in a dose-dependent manner by theophylline in AH130 cells. The maximum combined cytotoxicity was observed when AH130 cells were treated with IPN at 10^-7 M for 30 min before the exposure to MMC and, in this pretreatment condition, the uptake of MMC was enhanced in parallel with the increase of cyclic adenosine 3' : 5'-monophosphate (cyclic AMP) level in the cells. On the other hand, MMC, which had no stimulating effect on the intracellular cyclic AMP level, nevertheless maintained a high level of intracellular cyclic AMP elevated by IPN for a longer period than in the treatment with IPN alone and prolonged the period of acceleration of the uptake of MMC. In the in vivo combined treatment with IPN and MMC, the life span of AH44-bearing rats was prolonged and 2 out of 6 rats were cured, while the mean survival time of the rats treated with MMC alone was 11.3 d. These results indicated that the intracellular cyclic AMP, which is maintained at a high concentration for a long period by the combined action of IPN and MMC, enhanced the uptake and the antitumor effect of MMC.

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Rat colonic absorption of cefmetazole was increased significantly by calmodulin inhibitors such as phenothiazines and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) when they were coadministered at a concentration between 1 and 100 μM. The bioavailability of cefmetazole, determined by area under the blood concentration curve method, increased 20 to 30% by the coadministration of calmodulin inhibitors. It is speculated that the enhancing action of agents on rat colonic absorption of cefmetazole takes place by a paracellular route and coadminstration of sodium ion increases their actions.

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Experiments were conducted in order to examine the mechanism of changes in body temperature induced by phencyclidine (PCP) in mice. It is well known that morphine changes body temperature in a biphasic manner. PCP also produced hyperthermia at low doses (5 and 10 mg/kg) and hypothermia at high dose (40 mg/kg). The changes in body temperature induced by PCP were blocked by naloxone, a mu antagonist. Pretreatment with morphine (2.5 mg/kg), a mu agonist, or ethylketocyclazocine (EKC : 2.5 mg/kg), a kappa agonist, potentiated hypothermia induced by high dose of PCP. Effects of morphine and EKC on PCP-induced hypothermia were antagonized by naloxone. N-Allylnormetazocine (SKF 10047 : 20 mg/kg), a kappa and mu antagonist, antagonized PCP-and EKC+PCP-induced hypothermia but not morphine+PCP-induced hypothermia. Furthermore, Mr 2266, a kappa antagonist, antagonized PCP (10mg/kg)-induced hyperthermia and EKC+PCP-induced hypothermia. It is suggested that PCP may affect thermoregulation through mu and/or kappa opioid receptor mechanisms.

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The effects of bile salts on the calcium movements and the electrical activity of the guinea-pig taenia coli were investigated and compared with those of papaverine in order to explore the mechanisms of their spasmolytic action. Four bile salts, deoxycholate, chenodeoxycholate, ursodeoxycholate and cholate, as well as papaverine, dose-dependently relaxed the depolarized taenia coli. The bile salts and papaverine caused the acceleration of ⁴⁵Ca-efflux with the synchronous muscle relaxation and inhibited the cellular ⁴⁵Ca-uptake by the depolarized muscle preparation. The bile salts also inhibited the increased spike frequency and the developed tension in the depolarized taenia coli. Furthermore, the dose-relaxation curves for bile salts were shifted to the right as the external calcium ion was increased. These findings suggest that the bile salts, like papaverine, may exert their spasmolytic action through accelerating the Ca-efflux and inhibiting the Ca-influx of the smooth muscle cells.

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Pharmacokinetic relationships were developed to characterize a multi-exponential drug disposition and pharmacologic response time courses. The derived expressions were applied to serum and cerebral concentrations and the hypothermic response data, which were obtained after rapid intravenous administration of chlorpromazine hydrochloride to rats. The results of this study indicate that the magnitude of the pharmacologic effects of chlorpromazine such as decrease in metabolic heat production and increase in tail blood flow, at a given time, are logarithmic logistic functions of the cerebral chlorpromazine concentration at that time.

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The interaction of cholecystokinin (CCK) C-terminal peptides with the protein inhibitor (PK-I) of adenosine 3', 5'-cyclic monophosphate-dependent protein kinase (A-PK) was studied by immunoprecipitation using anti-PK-I antibody. The binding of CCK-4 peptide to PK-I was shown to be specific ; while CCK-4 enhanced precipitation of PK-I with antibody, it did not enhance precipitation of bovine serum albumin (BSA) by anti-BSA. The interaction of CCK-4 with PK-I is reversible and similar to that of urea but different from that of alkali. These results support the conclusion that CCK-C terminal peptides interact specifically with PK-I.

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In the present study, using trimethadione (TMO) as an indicator substrate, we estimated pre- and post-operative differences in hepatic drug-oxidizing capacity in patients with extrahepatic cholelithiasis. Only total and direct bilirubin values were significantly higher in preoperative patients than in the controls. After operative procedures, those parameters did not show significant differences from corresponding control values. The serum dimethadione (DMO)/TMO ratios estimated 4 h after administration of 4 mg/kg of TMO. Neither pre- nor post-operative serum DMO/TMO ratios were significantly different from those in the controls. These results suggest that the hepatic drug-oxidizing capacity in patients with extrahepatic cholelithiasis remains unchanged even though the bilirubin level deviated from normal.

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We studied the effect of cyclic guanosine 3', 5'-monophosphate (cyclic GMP) on p-aminohippurate (PAH) uptake by basolateral membrane vesicles isolated from rat kidney cortex. Cyclic GMP inhibited PAH uptake dose-dependently. Dibutyryl cyclic GMP inhibited the uptake of PAH to the same extent. However, cyclic adenosine 3', 5'-monophosphate, cyclic cytidine 3', 5'-monophosphate and guanosine monophosphate had no effect on PAH uptake by membrane vesicles. Therefore, the inhibition of PAH uptake was specific to cyclic GMP and not common to nucleotides. In the presence of probenecid, an inhibitor of PAH transport, cyclic GMP did not affect PAH uptake. Thus, cyclic GMP had an inhibitory effect on probenecid-sensitive PAH transport. Inhibition by cyclic GMP of PAH uptake by basolateral membrane vesicles as described this study may contribute to the decrease in PAH accumulation in kidney cortical slices caused by the cyclic nucleotide which we previously reported.

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