摘要:

The affinity and metabolism of alprenolol, a β‐receptor antagonist, in rat liver microsomes, perfused liver and in the conscious rat were studied. Alprenolol elicited a type I difference spectrum with a spectral dissociation constant, Ks, of 0.34 μM. The apparent Michaelis‐Menten constant, Kmin rat liver microsomes was 25 μM and in the 9000xg supernatant fraction 17 μM. In re‐circulating perfusions of rat liverin situalprenolol at an initial concentration of 4.3 μg/ml was rapidly eliminated from the perfusate with a clearance close to the flow rate of the perfusate. The concentration in the perfusate of total metabolites increased rapidly to a high level. In conscious rat with permanent cannulas the blood concentration of alprenolol was determined after intravenous and oral administration of 2.0 mg/kg. The bioavailability of orally given alprenolol was 4 per cent of the given dose. The elimination after intravenous administration was bi‐exponential with a half‐life time of the β‐phase of

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00735.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

An organic mercurial compound, methoxy‐ethyl‐mercury chloride (MEMC) has been studied for its subacute neurotoxic effects by means of EEG and evoked potentials, in male rats. Poisoning by MEMC during four weeks causes characteristic alterations of the electroencephalogram: i.e. increases the α1; β1; β2frequency, analysed by integration of spectral frequency. The amplitude and duration of the cortical evoked potentials were also c

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00736.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

Rats were given MnCl2.4H2O (8 mg/kg) intraperitoneally daily for 120 days, and then sacrificed by decapitation. The brain was removed and dissected into three regions; cerebral cortex, cerebellum and remainder of the brain. Enzymic studies were conducted in these regions and compared with control animals. The activities of acetyl choline esterase and adenosine deaminase were significantly reduced in all the three regions. The activity of monoamine oxidase was increased in the cerebellum while the activity of guanine deaminase decreased in the cerebellum and remainder of the brain. The analysis of the results allows no overall generalization in enzymic alterations induced by manganese chloride in the three regions of the rat brain.

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00737.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

Malathion induced changes in blood glucose, plasma electrolytes and glycogen content of different tissues have been investigated. Malathion was administered intra‐peritoneally in dose of 50 mg/100 g body weight to 12 hrs‐fasted rats. A significant increase of blood glucose and plasma sodium was observed during the first 6 hrs of treatment, whereas, the glycogen content of the liver, kidney, heart and spleen showed a marked increase during the next 6 to 24 hrs. No significant change in plasma potassium and brain glycogen content was observed at different time intervals. The possible role of the adrenal medulla in malathion induced biochemical changes is discus

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00738.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

The effect of corticosteroid on the rate of biotransformation of cyclophosphamide in man was studied. Two opposite effects could be demonstrated. The immediate effect consisted of an inhibition of the biotransformation probably due to the inhibition of the hepatic drug‐metabolizing enzymes whereas prolonged treatment with prednisone resulted in an increased rate of biotransformation of cyclophosphamide, probably due to the induction of the same enzyme syste

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00739.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

Wistar rats with Li‐induced polydipsia and polyuria (group 3) were deprived of water in order to examine their maximal urinary concentrating ability. For comparison, water deprivation was also achieved in rats with “polydipsia” induced by replacing the drinking water with 5 % glucose (group 1) and in rats with hereditary hypothalamic diabetes insipidus (group 2). The animals were totally deprived of water either for 72 hours or until 20 % loss of body weight had been obtained. Body weight, urine flow and urine osmolality were recorded every 6 hour, and serum osmolality at maximal dehydration. The urine osmolality was initially less than 250 mosm/kg in all groups. Maximal urine osmolality recorded during water deprivation was (1) 2732±100, (2) 1067±84, and (3) 1200±216 (S.D.) mosm/kg. Under the same conditions normal Wistar rats concentrated the urine to 3529±170mosm/kg. Terminal serum osmolality was (1) 310±1, (2) 346±9, and (3) 390 ±31 mosm/kg as compared to 307±2 mosm/kg in normal Wistar rats. During water deprivation, the urine flow was diminished more rapidly and to a lower level in group (1) than in groups (2) and (3). The results indicate that rats with Li‐induced polydipsia and polyuria exhibit marked impairment of the renal concentrating ability. Nothing in the results suggests Li‐polyuria to be secondary to a primary polydipsic action o

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00740.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

The effect of digoxin on the contractility of the nonfailing heart was studied in anaesthetized dogs receiving continuous infusion of digoxin 0.8 jig/kg/ min. The contractility, described by Vce5was increased to 30 % above control levels after infusion of 35 μg/kg of digoxin. From this point only an insignificant increase in contractility was obtained following futher infusion of digoxin. The myocardial content of digoxin, measured by a radio immuno method, was proportional to the cummulated dose and calculated to be about 140 ng/g tissue, when the maximal increase in contractility was achieved. The content of digoxin in the myocardium of 275 ng/g tissue was not associated with dysrhythmias

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00741.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

The metabolism and disposition of14C‐nortriptyline and14C‐imipramine in the rat was studied after intraperitoneal administration of single doses of the drug. With14C‐nortriptyline, it was found that concomitant administration of perphenazine caused a rise in plasma level and tissue concentration of unchanged nortriptyline. With14C‐imipramine, it was found that administration of perphenazine caused an increase in tissue concentration of imipramine, desipramine, and iminodibenzyl. At the same time total excretion by the faeces and the urinary excretion of glucuronides and other polar metabolites was decreased. The urinary excretion of imipramine‐N‐oxide was increased in perphenazine pretreated rats. These results indicate that perphenazine in rats inhibits the hydroxylation and/or glucuronide formation of imipramine, whereas demethylation, N‐oxidation, and dealkylation seem to be unaffected. Dose response studies showed that perphenazine and chlorpromazine have equivalent potency with regard to the increased tissue concentration of1

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00742.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

The differential renal excretion of phenoxyacetic acid, 2‐chlorophenoxyacetic acid, 4‐chlorophenoxyacetic acid,2,4‐dichlorophenoxyacetic acid (2,4‐D) and 2,4,5‐trichlorophenoxyacetic acid (2,4,5‐T) was measured in chickens by the method of Sperber (1948&1954). Doses of approximately 50 and 100 μmol of either test compound were infused during 3 min. into a leg vein and the amounts excreted by the two kidneys determined during consecutive 15‐min. periods. At the lower dose level the mean apparent tubular excretion fractions (EF) of the compounds, expressed as per cent of the dose, where 16.5, 22.9, 12.8, 11.3 and 4.2, respectively. All the values except that for 2,4,5‐T are sufficiently high to be indicative of tubular excretion. On increasing the dose, the EF values decreased, thus suggesting the involvement of a saturable mechanism. The test compounds proved to depress the excretion of phenol red, the effect being most mar

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00743.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY

摘要:

The highly lipid soluble β‐receptor blocking drug alprenolol interacts with high affinity with rat liver microsomal cytochrome P‐450, is rapidly metabolized in the liver and exhibits a marked liver “first pass elimination” (FPE) in the rat. It thus has a low oral bioavailability in this species. In order to investigate the possible role of the cytochrome P‐450 system in the FPE we studied the influence of the three P‐450 inhibitors SKF 525‐A, imipramine and metyrapone and of phenobarbital treatment on the disposition kinetics of alprenolol in a series of experimental models. Alprenolol rapidly gave rise to a type I spectral change on addition to intact liver cells, indicating a rapid hepatic uptake. The maximal magnitude of this spectrum increased about twofold after phenobarbital treatment of rats in both microsomes and isolated liver cells. Imipramine, SKF 525‐A and metyrapone partly displaced3H‐al‐prenolol from non‐metabolizing partly purified cytochrome P‐450 and liver cell preparations (20°). Imipramine and SKF 525‐A were about equally effective in this respect whereas metyrapone was much less potent. At 37° the metabolism of alprenolol was rapid and of about similar activity (per nmoles of cytochrome) in liver microsomes, isolated liver cells and in the perfused liver (at a high dose). The Km‐value was similar in microsomes and in isolated liver cells. A similar metabolic inhibitory pattern was found in microsomes and isolated liver cells. SKF 525‐A was the most efficient inhibitor followed by imipramine and then metyrapone. The same inhibitory pattern was found for the hepatic extraction of alprenolol. Moreover, the hepatic extraction of alprenolol was dose dependent. Imipramine in a high dose increased the area under the blood concentration curve by a factor of ten after oral administration of alprenolol in the conscious rat. The above findings suggest that cytochrome P‐450 is, at least partly, responsible for the degree of hepatic extraction and metabolism (FPE) of alprenolol. This view was also supported by the findings that the perfused liver showed an increased capacity for the extraction and metabolism of alprenolol after phenobarbital treatment. The cytochrome P‐450 system may influence the hepatic extraction of alprenolol in rat liver by providing an intracellular “high affinity binding pool” for the unchanged drug. The subsequent metabolic step seems to be important since it “unloads”

ISSN:0001-6683    

DOI:10.1111/j.1600-0773.1974.tb00744.x

出版商:Blackwell Publishing Ltd    

年代:1974

数据来源: WILEY