Influence of several bacterial and viral vaccines on hepatic drug metabolism in mice

Pentobarbital-induced sleeping time was found to be significantly prolonged in mice within at least 4 days following either whooping cough, tetanus, rubella or poliomyelitis vaccination. By contrast, barbital-induced sleeping time remained unaffected, These findings provide further evidence of a correlation between inhibition of liver drug metabolizing enzymes and stimulation of the immune response.     

Effect of benzene on hepatic drug metabolism and ultrastructure

Benzene metabolism was stimulated in rat liver microsomes after treatment of rats with benzene but not after treatment with phenol or resorcinol. Pretreatment of rats with hydroquinone, pyrocatechol and pyrogallol inhibited benzene metabolism in vitro. Single large doses of benzene also stimulated the metabolism of zoxazolamine, neoprontosil and p-nitrobenzoic acid but not that of hexobarbital or chlorpromazine. During the course of daily benzene treatments, the metabolism of zoxazolamine was stimulated after 7 days, while 14 days of treatment was necessary for benzene and neoprontosil. The metabolism of hexobarbital and p-nitrobenzoic acid was inhibited after 14 days. Electron microscopic studies of the liver showed proliferation of the smooth endoplasmic reticulum (SER) after 7 and 14 days of benzene treatment. It is concluded that benzene, not its hydroxylated derivatives, is probably responsible for benzene-induced microsomal stimulation and that benzene-induced proliferation of SER does not ensure an increase of the metabolism of all drugs.     

Effect of acute and chronic exercise on hepatic drug metabolism

Recent research indicates that physical exercise and fitness are new host factors with impact on hepatic drug metabolism, contributing to the intra- and interindividual variation in drug response. Moderate to heavy physical exercise for a few hours reduces liver blood flow as assessed by indocyanine green clearance, leading to a decreased elimination of drugs exhibiting flow-limited metabolism (high clearance drugs) such as lignocaine (lidocaine). However, hepatic elimination of drugs exhibiting capacity-limited metabolism (low clearance drugs) such as antipyrine (phenazone), diazepam and amylobarbitone (amobarbital) is not affected by acute physical exercise. Improved physical fitness as expressed by the maximum oxygen uptake seems to increase the elimination rate of the low clearance drug antipyrine and possibly also aminopyrine, while investigations of the biotransformation of high clearance drugs are contradictory. The sum of research in this recent field is rather limited and the mechanism whereby changes in physical fitness influence hepatic drug metabolism needs to be established. It is not known if other liver functions are changed. If the findings also apply for drugs with a low therapeutic index, there may be a risk of exercise-induced changes in drug efficacy and toxicity. It is suggested that future studies on host factors influencing drug metabolism should include information on physical activity.     

伤寒疫苗的现状及展望

伤寒仍是发展中国家的主要公共卫生问题,控制伤寒的最有效措施是接种疫苗.此文介绍了早期伤寒疫苗和现行伤寒疫苗的的安全性和有效性,讨论了伤寒Vi多糖结合疫苗的研发现状及应用前景.     

Effect of tacrine hydrochloride on hepatic drug metabolism.

The aim was to assess tacrine hydrochloride (THA) as an inhibitor of rat hepatic oxidative enzymes. A model of hepatic microsome oxidative metabolism was established using antipyrine (AP) incubated with NADPH. AP and its metabolites, 3-hydroxymethyl antipyrine (HMA). 4-hydroxy antipyrine (OHA) and norantipyrine (NORA) were measured by high performance liquid chromatography (HPLC). Aliquots of 200, 400 and 600 microg/ml antipyrine were incubated with the microsomal preparation alone, with 20 microg/ml cimetidine or with 40, 80 or 200 microg/ml THA. Cimetidine inhibited HMA production by 35-38% (P<0.001) and OHA production by 49-52% (P<0.001). Incubation with the 3 concentrations of THA inhibited HMA production by 17%, 24% and 41% (P<0.001) and OHA production by 52%, 55% and 79%, respectively (P<0.001). NORA was identifiable when antipyrine was incubated with NADPH alone, but could not be identified after incubation with either cimetidine or THA. This study has shown that THA causes the inhibition of AP metabolism to HMA, OHA and possibly NORA. We suggest THA is an inhibitor of three different hepatic microsomal cytochrome P-450 enzyme sub-families.     

Effect of cold exposure on drug action and hepatic drug metabolism in the rat

Exposure of male rats to a temperature of 4°C for 4 days decreased the sleeping time response to hexobarbital and meprobamate, but not to barbital. Plasma concentrations of these drugs present at the time the righting reflex was regained were lower in the cold-exposed rats, indicating that the observed decrease in sleeping time was not due to decreased central nervous system sensitivity to these agents. The onset time of hexobarbital, meprobamate and barbital hypnosis was similar in cold-exposed and control rats, suggesting that altered drug absorption is not responsible for the observed differences in duration of drug response. The decline of brain and plasma concentrations of zoxazolamine was more rapid in the cold-exposed animal. The metabolism of hexobarbital and aminopyrine was significantly elevated in isolated perfused livers from cold-exposed rats. Hepatic microsomal N-demethylase activity, hexobarbital and meprobamate oxidation, CO-binding pigment, and NADPH-cytochrome c reductase activity were increased in the cold-exposed rat. Experiments with 2-¹⁴C-glycine indicated that the in vivo incorporation of this isotope into hepatic microsomes was increased significantly in the cold-exposed rat. These results indicate that cold exposure stimulates hepatic drug metabolism and suggest that this stimulation is mediated via an accelerated synthesis of the hepatic drug-metabolizing system.     

The effects of SKF 525-A on hepatic glycogen and rate of hepatic drug metabolism

The level of hepatic glycogen and rates of certain drug metabolisms were studied after administration of SKF 525-A (β-diethylaminoethyl diphenylpropyl acetate HCl) to adult rats. SKF 525-A inhibits hepatic drug metabolism within 1 hr, and a significant effect is seen up to 24 hr after administration. SKF 525-A lowers hepatic glycogen to a minimum level in 8 to 12 hr. The recovery of hepatic glycogen and rate of hepatic drug metabolism to control values occurs at the same time after administration of SKF 525-A. The effects of SKF 525-A on certain enzymes of hepatic glycogenesis and glycogenolysis were also studied.     

Anti-inflammatory agents and inducibility of hepatic drug metabolism.

Two rat liver cytosolic aldehyde dehydrogenases, ALDH1 and ALDH3c, are of particular interest because they are inducible by different classes of xenobiotics. ALDHI is mainly increased by phenobarbital-type inducers; polycyclic aromatic hydrocarbons (PAHs), such as 3- methylcholanthrene (3MC), increase ALDH3c enzyme activity in all rat species currently tested. In addition, ALDH3c has been found to reflect the subfamily CYPIA of cytochrome P-450, as well as other enzymes functionally related to the aryl hydrocarbon receptor (the "Ah-receptor enzyme battery"), which is activated by the same type of inducers. In the present study we investigated whether the induction of ALDH3c might be connected with a chemically produced aseptic inflammation of the hepatocyte. To answer this question, we examined the relationship between the induction of ALDH3c by 3MC and the arachidonic acid cascade. Different non-steroid anti-inflammatory drugs (NSAIDs) were tested in combination with 3MC and in post-treatment. The 3MC-induced ALDH3c activity was significantly diminished by the co-administered anti-inflammatory agents. Two microsomal enzyme activities (ethoxyresorufin-O-deethylase, EROD; aryl-hydrocarbon-hydroxylase, AHH) were also decreased. Similar results were obtained with NSAIDs administered to animals pre- treated with 3MC, as far as the ALDH3c activity was concerned, but not for the microsomal enzyme activity (EROD and AHH). In conclusion, the induction of ALDH3c, after PAH treatment, may be related to an aseptic inflammation of the hepatocytes. This effect is reduced by commonly used steroid and non-steroid anti- inflammatory drugs, and although the mechanism of inhibition has not yet been elucidated, it appears likely that ALDH3c and CYP1A activities are associated with the "acute phase" response.     

Effect of dibromotetrafluoroethane inhalation on hepatic drug metabolism in mice

Inhalation of dibromotetrafluoroethane, 0.63 to 1.0%, for 5 hr daily, for 3 or 4 days, reduced hexobarbital sleeping time and zoxazolamine paralysis time 2-fold in mice. Increased metabolism of hexobarbital and zoxazolamine by the hepatic 9000 g microsomal supernatant fraction prepared from exposed mice correlated well with the effects determined in vivo. Addition of 2,4-dichloro-6-phenyl-phenoxyethyldiethylamine (SKF 525-A) to the hepatic 9000 g microsomal supernatant fraction prevented the dibromotetrafluoroethane-induced increase in hepatic drug metabolism.     

Effect of zinc on hepatic drug metabolism under ethanol toxicity

The effects of zinc on drug-metabolizing enzymes in the liver were examined in male Wistar rats following ethanol intoxication. Rats were orally fed 3 mL of 30% ethanol daily for either two, four, or eight weeks and were orally administered zinc sulfate (ZnSO4.7H2O) at a dose level of 227 mg/L. Levels of reduced glutathione (GSH) and the activities of cytochrome P-450, cytochrome b(5), NADPH cytochrome-C-reductase and glutathione-S-transferase (GST) were determined in liver after two, four, and eight weeks. Significant elevation was observed in the activities of the enzymes of the mixed function oxidase system in response to toxicity induced by ethanol at all the intervals. These effects of were ascribed to the enhanced activity of the microsomal ethanol oxidizing system and the associated increase in reactive oxygen species production. Zinc supplementation to these ethanol-intoxicated animals resulted in normalization of these elevated values significantly, but still they do not attain normal levels. Significant increase was observed in reduced glutathione content in animals after four and eight weeks of ethanol feeding, which appeared to be further elevated in combined zinc and ethanol treatment. Significant elevation in the activity of GST was illustrated on ethanol-fed animals at all the three treatment intervals. Furthermore, the activity of this enzyme was only moderately normalized following zinc treatment. This was accredited to the antioxidant potential of zinc, as well as its ability to induce metallothionein content, which provide protection against the toxic effects of ethanol. To conclude, zinc was able to normalize the effects of ethanol in the liver.     

Effect of phencyclidine on hepatic drug metabolism in the rat

Phencyclidine, an anesthetic used in experimental animals, was examined for its effect on hepatic drug metabolism. Treatment of male rats for 4 days with phencyclidine (50 mg/kg/day, ip) caused significant increases in the rate of metabolism of hexobarbital, aminopyrine, and zoxazolamine in vitro by the 10,000 g hepatic supernatant fraction. Metabolism of p-nitroanisole in vitro was not altered by the drug treatment. Significant shortening of hexobarbital sleeping time was observed after phencyclidine treatment. Zoxazolamine paralysis time was increased by the drug treatment. The discrepancy between the zoxazolamine studies in vivo and in vitro appear to be due to alteration of the sensitivity of the rat to the paralyzing action of zoxazolamine since plasma concentrations at the time of recovery from zoxazolamine paralysis were lower in the treated animals.     

The use of single sample clearance estimates to probe hepatic drug metabolism: Handprinting the influence of phenobarbitone on human hepatic drug metabolism

1. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Clearance estimates were calculated in healthy young adult male volunteers either taking no pretreatment, or taking phenobarbitone (PB) 100?mg nightly for 3 nights. This intermittent regimen (3 nights on, followed by 4 nights off) was repeated for at least 3 consecutive weeks prior to challenge with an individual probe.

2. Valproic acid was selected as a probe of both peroxisomal and microsomal β-oxidase activity; antipyrine, phenytoin, quinidine, and carbamazepine were selected as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyl transferase activity.

3. Clearances of all probes except lorazepam, theophylline and phenytoin were approximately 20-30% faster in PB-treated than in control subjects; however, only in the case of carbamazepine did the increased clearance approach statistical significance. Neither phenytoin nor theophylline clearances were increased by PB.

4. A clearance index (probe CL for PB-treated subjects divided by probe CL for untreated subjects) was calculated for each probe, and an ordinal transformation of the log of the resultant ratio was plotted for each probe giving rise to a ‘handprint' of the effect of PB on drug-metabolizing activity.     

Influence of allopurinol on drug metabolism in man

1. Elimination rates of phenylbutazone and warfarin after single oral doses in human volunteers, and steady-state plasma concentrations of these drugs in patients have been measured before, during and after administration of allopurinol.2. Allopurinol, in usual clinical doses, had no significant influence on the elimination rate of either drug in the group of volunteers as a whole although in a few individuals an apparent inhibitory effect was observed.3. No significant changes in the steady-state plasma concentrations of either phenylbutazone or warfarin were observed in patients during the administration of allopurinol.4. It is concluded that although allopurinol may have an apparent inhibitory effect on drug elimination in a few individuals, its administration to most patients on anticoagulant therapy is unlikely to alter dose requirements.     

Impairment of hepatic drug metabolism in alcoholics.

1 The effects of chronic ethanol intake on the elimination kinetics of antipyrine were determined in nineteen male alcoholic subjects with comparison made to fourteen male volunteers. 2 Half-lives were longer and clearance values less in the alcoholic group. 3 Significant rank correlations were found between half-life and clearance when compared with various biochemical parameters of liver function measured in the plasma of the alcoholics. 4 These results show that a significant proportion of the alcoholics studied had impaired hepatic drug metabolizing capacity and that the activity of hepatic microsomal enzymes may be related to the extent of ethanol induced liver damage in these subjects.     

Effect of pregnancy on hepatic microsomal drug metabolism in rabbits and rats

In Dutch-belted rabbits, pregnancy caused several-fold decrease of in vitro hepatic microsomal aminopyrine, benzphetamine, and hexobarbital biotransformations. In pregnant Sprague-Dawley rats, various kinds of expressing the in vitro rates of hexobarbital biotransformation (per mg of microsomal protein, g of liver, 100 g of body weight) indicated unchanged or slightly elevated microsomal enzyme activity. In vivo, the course of hexobarbital blood levels after i. p. hexobarbital sodium, 100 mg/kg, indicated that the fate of hexobarbital was not primarily determined by the small changes of microsomal enzyme activity but, rather, by changed hexobarbital distribution. Different ways of expressing in vitro rates of aniline biotransformation showed decreased or unchanged enzyme activity during pregnancy and in vivo experiments indicated that these changes did not affect aniline metabolism in living rats. The results pointed out marked species differences in the effect of pregnancy on drug metabolism. Interpretation of in vitro biotransformation data for living animals suggested that with different substrates, microsomal enzyme activity and distribution, respectively, may exert different effects playing either significant or apparently minor role in drug disposition.Supported in part by U.S. Public Health Grant NIGMS 12,675.