The effect of di-(2-ethylhexyl) phthalate (DEHP) on oxidative phosphorylation of isolated rat liver mitochondria was investigated. DEHP at concentrations of 20-1000 μM had no effect no state 4 respiration, but at 40 μM, DEHP decreased the rate of state 3 respiration by about 20%. Although DEHP had no effect on electron transport through the respiratory chain, it decreased the rate of adenosine triphosphate (ATP) synthesis. Its inhibition of ATP synthesis showed a similar concentration dependence to that of state 3 respiration. Furthermore, DEHP at 40 μM inhibited the uptake of [³H] adenosine diphosphate into mitochondria. DEHP also retarded the action of cationic uncoupling agents, which are known to modify the 29000-dalton protein involved in adenine nucleotide exchange. These results suggest that DEHP affects the activity of adenine nucleotide exchange and consequently partially decreases the rate of state 3 respiration. The action of DEHP on the 29000-dalton protein involves a protective effect against mitochondrial damage induced by hydrophobic cations or heavy metal cations.

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Mice showed a marked suppression of motility when placed in the same environment where they had been given electric shocks (ES) 24 h before. This conditioned suppression of motility (CS) was attenuated by the administration of cycloheximide (CXM, 25-150 mg/kg) immediately after ES treatment in a dose-dependent manner. CXM (50 mg/kg) administered 1 h after ES failed to attenuate the CS. These effects seem to be caused by retrograde amnesia. Furthermore, the amnesic action of CXM was antagonized by naloxone (10 mg/kg), which did not affect CS. Physostigmine (0.2 mg/kg), propranolol (1 mg/kg) and cyproheptadine (2 mg/kg) did not antagonize CXM-induced amnesia significantly. In the same way, the amnesia-inducing actions of phencyclidine and scopolamine were detected. The CS method seems to be useful to examine learning and memory performances in animals and has the advantage that evaluation is extremely easy.

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The effects of cimetidine on the disappearance from plasma, plasma protein binding, tissue distribution, tissue binding in vitro and uptake by erythrocytes of lidocaine were studied in rats. The plasma disappearance of lidocaine after a 10 mg/kg bolus injection was analyzed by a two-compartment open model. In the cimetidine-treated rats (50 mg/kg bolus injection, the plasma total body clearance (Cl_tot), the volume of distribution at the steady state (V_dss) and the elimination rate constant of the central compartment (k_el) of lidocaine decreased by 27, 28 and 32% of those of the non-treated rats, respectively. The plasma concentration of lidocaine at the steady state, after a loading dose (7.62 mg/kg body weight) followed by an infusion (0.16 mg/min/kg), increased from 1.62 to 2.69 μg/ml after cimetidine treatment. The tissue-to-plasma concentration ratio (K_p) in spleen, stomach and skin decreased to 64, 62 and 62% of the values of the non-treated rats. In addition, the blood-to-plasma concentration ratio (R_b) decreased by 26% in cimetidine-treated rats. In vitro tissue-to-plasma concentration ratios (K_{p, vitro}) of lidocaine in spleen, stomach and skin homogenate were decreased to 58, 45 and 68% by cimetidine treatment. In these tissues, the percentage decreases of K_{p, vitro} agreed with those of K_p determined in vivo. The decrease of K_p by cimetidine treatment may be due to the inhibition of tissue binding of lidocaine. The uptake of lidocaine by erythrocytes was decreased by cimetidine treatment. The pH profile of uptake was shifted to the higher pH side by the addition of cimetidine, indicating a decrease of the pH difference between intra- and extracellular spaces.

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In order to evaluate the effect of piretanide on the renal transport of water and osmotic substances, a clearance study was carried out in well hydrated rabbits. After intravenous bolus administration of piretanide, glomerular filtration rate, proximal tubular clearance and urine flow rate, as well as the pharmacokinetics of piretanide, were determined. A pharmacokinetic and pharmacodynamic link model which was developed in the previous paper was applied to the present experimental results. The results indicated that the effect of piretanide on the renal transport of water and osmotic substances in the hydrated rabbits was reasonably described by the model. The model analysis suggested that the diuretic response to piretanide was attributable to the inhibition of reabsorption of electrolytes in the proximal tubule, as well as in the loop of Henle.

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The effects of continuous stimulation of salivation on salivary, renal and systemic clearances of lithium were investigated following bolus intravenous administration of lithium chloride (0.145 meq/kg) in three beagle dogs. The salivation was frequently stimulated with citric acid solution, then parotid saliva and mandibular-sublingual saliva were collected separately by means of permanent fistulae. Although the continuous stimulation of salivation markedly increased the salivary clearance of lithium, no significant change was observed in plasma concentrations or systemic clearance of lithium. This was because the decrement in the renal clearance of lithium canceled out the effect of increased salivary clearance. It is suggested that the reabsorption of lithium in the renal tubule was enhanced under the continuous stimulation of salivation, and this seemed to be caused by loss of water or sodium through the salivary glands.

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When male ddY mice were treated with consecutive doses of 10 and 100 mg/kg of miconazole (MCZ) or ketoconazole (KCZ), imidazole-containing antimycotics, once a day for 3 d, a dose-dependent shortening of pentobarbital sleeping time was observed for MCZ, while no change in the sleeping time was observed for KCZ. Even at a low dose (10 mg/kg), MCZ significantly increased cytochrome P-450 content and reduced nicotinamide adenine dinucleotide phosphate cytochrome creductase activity. Simultaneously, hydroxylase activities of testosterone as a model of endogenous steroids, and aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities were increased, while KCZ lacked inducing properties even at a high dose (100 mg/kg). The change in hepatic oxidative metabolism of cortisol (F) in a patient before, during and after treatment with progressively increasing doses of 2-10 mg/kg/d of MCZ for 14 d was examined by monitoring urinary 6β-hydroxycortisol (6β-OHF), an oxidative metabolite of F. The ratio of 6β-OHF to F in 24-h urine decreased by 15% from the original level on day 1, and then it began to increase on day 7 to reach 2.4 times the original level on day 14. These results suggest that MCZ, but not KCZ, has inducing activity for hepatic cytochrome P-450-dependent oxidative metabolism of steroids and xenobiotics, in addition to its known inhibitory activity.

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The effects of prenatal administration of phencyclidine (PCP) on the learning and memory processes of rat offspring were investigated at doses below the level for producing malformations. The offspring prenatally treated with PCP (10 or 20 mg/kg) on days 7 to 17, as well as on days 7 to 21 of gestation, showed disruption of the acquisition of passive avoidance response and pole-climbing avoidance response at the ages of 4 and 7 weeks, respectively. The brain weight of the offspring prenatally treated with PCP was significantly decreased. These results suggest that prenatal PCP administration impairs learning and memory processes of passive and active avoidance tasks and that more attention should be given to the developmental toxicity of PCP.

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The bioavailability of propranolol applied to the oral mucosa was examined in the hamster. The capacity of hamster cheek pouch, used as a model of keratinized oral mucosa, to metabolize propranolol in vitro is enormously lower than that of the liver. Significant amounts of propranolol absorbed from the small intestine were metabolized to naphthoxylactic acid and 4-hydroxypropranolol (4HP) during the passage through the intestinal wall, and then the greater portion of unchanged propranolol and almost all 4HP were subsequently metabolized by hepatic first-pass elimination in vivo. The systemic bioavailabilities of propranolol after the intra-small-intestinal loop and the intra-cheek-pouch administrations were 8.4% and 88.5%, respectively. The bioavailability of propranolol was improved further (to 97.1%) by a 1-h pretreatment of the cheek pouch with 5% 1-dodecylazacycloheptan-2-one (Azone)-emulsion. Bioadhesive film-dosage forms of propranolol were prepared with hydroxypropyl-cellulose. Both the in vitro permeation and the in vivo absorption of propranolol across the cheek pouch were enhanced by the incorporation of Azone to the film-dosage form.

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Metabolism of cannabidiol (CBD), one of the major components of marihuana, was studied in the guinea pig both in vitro and in vivo. Analyses of metabolites by gas chromatography and gas chromatography-mass spectrometry proved that cannabielsoin (CBE) was formed from CBD as a novel metabolite, and that the amount was about one-sixth of 7-hydroxy-CBD, which was the most abundant metabolite under in vitro conditions in the presence of microsomal monooxygenase (cytochrome P-450). CBE was also found in the liver of the guinea pig that was given CBD (100 mg/kg) intraperitoneally 1 h before sacrifice. The effects of CBE on pentobarbital-induced sleep and body temperature were assessed in the mouse ; CBE possessed little activity in either case.

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Changes in the mode of drug excretion in obstructive jaundice (OJ) were investigated in rats with experimentally induced OJ using a non-metabolized, highly-biliary-excreted antibiotic, cefpiramide (CPM). In OJ rats, biliary excretion of the drug was markedly diminished, while the urinary excretion was increased. The change in the mode of CPM excretion was examined in detail. It seems that the biliary excretion of CPM was decreased owing to the diminished biliary clearance in OJ rats. On the other hand, CPM binding to plasma proteins was decreased in the disease state. This change in the protein binding would be due to both the decreased albumin concentration and the accumulation of binding inhibitors in the plasma of diseased rats, and the decreased protein binding would be related not only to the increase in the volume of distribution but also to the increase in the renal clearance.

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