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Biomedical subjects

D D Breimer

Publications and source records attributed to D D Breimer.

At least 289 records · Page 16Linked to original sources
PubMed1981

The metabolic fate of 1',2'-epoxyhexobarbital in the rat.

1. In urine of rats treated with 1',2'-epoxyhexobarbital, unchanged compound and six metabolites were identified: 1,5-dimethylbarbituric acid, which is the end product of an epoxide-diol pathway, two stereochemically different 3'-hydroxy-1',2'-epoxyhexobarbitals, a hydroxyfuropyrimidine, 3'-hydroxyhexobarbital and 3'-ketohexobarbital. 2. The analytical methods used were based on capillary g.l.c. with nitrogen-selective or mass spectrometric detection. Identification was by electron impact and chemical ionization mass spectrometry. All the reference compounds needed for comparison were synthesized. 3. The mean plasma elimination half-life of 1',2'-epoxyhexobarbital after intra-arterial administration to the rat was 13.7 +/- 1.5 min (mean +/-S.D.; n = 3). A total body clearance of 35.2 +/- 9.6 ml/min (mean +/- S.D.) was calculated, which includes renal clearance of unchanged epoxide. 4. In rat liver microsomal preparations it was demonstrated that 1',2'-epoxyhexobarbital is hydrated by epoxide hydratase. With 1 mM 1,1,1,-trichloropropene-2,3-oxide (TCPO) this enzymic reaction could be inhibited completely. 5. On administration of the individual metabolites of the epoxide to rats, no evidence was found for their possible intermediacy in the formation of 3'-hydroxy- or 3'-ketohexobarbital, which are major metabolites of hexobarbital.

Animals↗
PubMed1981

Pharmacokinetics of etomidate in surgical patients.

Eight adult surgical patients received a single i.v. injection of etomidate-base (mean 0.22 mg.kg(-1)). Venous blood samples were drawn at frequent intervals for up to 10 hr following drug administration. Plasma concentrations of etomidate were measured with a newly developed capillary gas chromatographic method. Plasma concentrations fitted best to an open three compartment pharmacokinetic model by a non-linear regression computer programme. The following mean parameters were computed: distribution half-life 2.8 + or - 2.3 min, half-life of the alpha-phase: 22.3 +or - 10.4 min and half-life of the beta-phase 208.8 + or - 64.9 min, distribution volume 3.68 + or - 0.66 l.kg(-1) (Vd area) and 2.16 l.kg(-1) (Vdss) and plasma clearance 879 + or - 135 ml.min(-1). High tissue uptake is indicated by the rapidity and the large volume of distribution. Etomidate is rapidly redistributed from the central to peripheral compartments and rapidly eliminated by metabolism.

Adult↗
PubMed1980

Biotransformation and spectral interaction of xenobiotics with subcellular fractions from Drosophila melanogaster.

Several rapid bioassays are in use to detect, by means of mutagenicity, the formation of reactive metabolites from foreign compounds during their metabolism in the organism. Of these bioassays, the fruitfly Drosophila melanogaster was investigated with respect to its capacity to biotransform xenobiotics. By spectral analysis it was shown that in microsomal preparations of Drosophila the cytochromes P-450 and b5 are present. Microsomes appeared to possess aryl hydrocarbon hydroxylase and epoxide hydratase activities, while post-microsomal supernatants were able to conjugate appropriate compounds with glutathione and phosphate. As yet, glucosyl- and sulfotransferase activities can not be detected. The activities are compared to similar activities in rat liver.

Animals↗
PubMed1980

Disposition of hexobarbital in intra- and extrahepatic cholestasis in man and the influence of drug metabolism-inducing agents.

The pharmacokinetics of intravenously infused hexobarbital was studied in 10 patients with intrahepatic cholestasis and in 9 with extrahepatic biliary obstruction. The results were compared with those obtained in 16 healthy young volunteers and 5 older patients with normal liver function. After infusion, the plasma concentrations showed a rapid initial decline (alpha-phase) and subsequently a slower decrease (beta-phase). The half-life of a latter phase was 323 +/- 84 min in the healthy group, 357 +/- 151 min in the patients with intrahepatic cholestasis and 344 +/- 115 min in the group with biliary obstruction; the clearances were 3.41 +/- 0.90, 4.08 +/- 1.95 and 3.81 +/- 1.97 ml x min-1 x kg-1, respectively. The differences were not statistically significant. The mean volume of the central compartment of distribution and the steady state volume of distribution were not significantly different. In two patients hexobarbital clearance during cholestasis was greater than after it had subsided. After treatment of 11 patients with cholestasis with drug metabolism-inducing agents (phenobarbital, rifampicin or phenytoin), the half-life of hexobarbital was significantly shortened and the mean value of hexobarbital clearance was more than doubled.

Adult↗
PubMed1980

Developmental aspects of hepatic glutathione S-transferase activities in male rats.

The postnatal development of glutathione S-transferase activities was investigated in post-microsomal supernatants of the livers of male rats. A period of up to the age of 200 days was covered, using styrene 7,8-oxide as the electrophilic substrate for the transferase. Activity in animals on the day of delivery was small but significantly above the level of spontaneous conjugation. During 5 weeks postpartum the specific activity increased regularly to about sixfold when expressed as per mg of cytosolic protein, thereafter the activity slightly decreased. During the 5th postnatal week a sudden decrease in activity was observed, but it returned to the original value within about 5 days. The effect of weaning on this phenomenon was studied by comparing weaned with non-weaned rats in an investigation of glutathione S-transferase maturation in the 4th and 5th week postpartum, using styrene 7,8-oxide and 1-chloro-2,4-dinitrobenzene as the electrophilic substrates. Weaned rats exhibited the decrease in activity only when styrene oxide was the substrate. It is concluded that glutathione S-transferase levels in rat liver are low at birth, and develop gradually during the first 5 postnatal weeks. Transferase activities towards styrene oxide and chlorodinitrobenzene appears to mature independently and are partly associated with weaning.

Age Factors↗
PubMed1980

Preliminary studies on the ability of Drosophila microsomal preparations to activate mutagens and carcinogens.

Subcellular fractions from Drosophila melanogaster, known to have several xenobiotic-metabolizing enzymatic activities, were investigated with respect to their ability to biotransform compounds that require metabolic activation before exerting mutagenic effects. Nitrofurazone, dimethylnitrosamine, cyclophosphamide and 2-acetylaminofluorene were activated to mutagens upon incubation with Drosophila microsomes or 20000 x g supernatant: mutagenicity was observed in Chinese hamster ovary cells, Escherichia coli strains 343/113/R-9 and 343/113/uvrB, and Salmonella typhimurium TA1538. Under the conditions used, microsomal preparations of Drosophila were not able to activate benzo[a]pyrene to a mutagen for Salmonella typhimurium TA98. The spectrum of mutagenic effects observed shows some correlation with the known mutagenicity of these compounds in vivo in Drosophila melanogaster. Drosophila microsomes appeared to be at least as active as rat-liver microsomes when compared in this type of mutagenicity testing.

Animals↗
PubMed1980

Mutagenic activation of dibromomethane and diiodomethane by mammalian microsomes and glutathione S-transferases.

The influence of mammalian metabolizing enzymes on the mutagenic activity of dibromomethane and diiodomethane was investigated by using Salmonella typhimurium strain TA100 as indicator. The 2 compounds are known to be metabolized via an oxidative pathway catalysed by microsomal enzymes as well as through direct enzymatic conjugation with glutathione; both pathways possibly give rise to reactive electrophilic intermediates. In mutagenicity plate assays with pre-incubation, dibromo- and diiodo-methane were directly mutagenic towards strain TA100; their mutagenic activity was enhanced upon incubation either with rat-liver microsomes or with the cytosol fraction of the same organ, containing the glutathione S-transferases. These data can be taken as an indication that both microsomal oxidation and conjugation to glutathione are indeed responsible for the mammalian mutagenic activation of dihalomethanes.

Biotransformation↗
PubMed1980

Antipyrine metabolite formation in children in the acute phase of malnutrition and after recovery.

1. The plasma elimination rate of antipyrine and the urinary excretion of antipyrine and its primary metabolites 4-hydroxy-antipyrine, norantipyrine, 3-hydroxymethyl-antipyrine and 3-carboxyantipyrine were measured in five children in the acute phase of malnutrition and after recovery. The results were compared with those obtained in 3 normal children. 2. Upon nutritional rehabilitation antipyrine clearance increased from 0.65 +/- 0.14 ml min-1 kg-1 to 1.07 +/- 0.20 ml min-1 kg-1. 3. The urinary excretion of 4-hydroxy-antipyrine increased from 6.1 +/- 4.5 to 14.7 +/- 5.9%, norantipyrine from 8.8 +/- 5.7 to 14.3 +/- 5.4 and 3-hydroxy-methyl-antipyrine from 11.8 +/- 8.3 to 20.5 +/- 5.6% (% of dose/24h urine). Excretion of unchanged antipyrine decreased from 5.2 +/- 3.7 to 2.7 +/- 0.9% dose. The metabolite profile (ratio between the amounts of the various metabolites excreted) was not significantly different. 4. It is concluded that malnutrition decreases the rate of antipyrine metabolism, but it does not affect the three oxidative pathways differently.

Acute Disease↗
PubMed1980

The epoxide-diol pathway in the metabolism of vinylbital in rat and man.

1. In urine of rats given vinylbital (5-vinyl-5-(1'-methylbutyl)barbituric acid) i.p., unchanged vinylbital and its devinylated metabolite, 5-(1'-methylbutyl)barbituric acid, were identified. Rats synthetic 1',2'-epoxyvinylbital excreted the same compound as a major metabolite. No unchanged epoxide, nor 1',2'-dihydroxyvinylbital, could be identified in the urine of rats treated with vinylbital or its epoxide. 2. Attempts to synthesize 1',2'-dihydroxyvinylbital from 1',2'-epoxyvinylbital by acidic hydrolysis revealed that this possible metabolite decomposes readily to 5-(1'-methylbutyl)barbituric acid by a 'retro-aldol type' reaction. 3. In rat liver microsomal preparation 1',2'-epoxyvinylbital is readily hydrated by epoxide hydratase, but this reaction is almost completely inhibited by 0.8 mM 1,1,1-trichloropropene-2,3-oxide (TCPO). This finding and the identification of 5-(1'-methylbutyl)barbituric acid as end-product of this enzyme reaction provides further evidence for the existence of an epoxide-diol pathway in the metabolism of vinylbital. 4. Vinylbital and its devinylated metabolite are excreted in 36 h urine of rats treated with vinylbital, to an extent of 0.6 +/- 1.7% of the dose (n = 5), respectively. Upon administration of 1',2-epoxyvinylbital, 59.8 +/- 14.2% of the dose (n = 5) was excreted as 5-(1'-methylbutyl)barbituric acid. 5. In 60 h urine of three human volunteers who had taken 150 mg of vinylbital orally, 2.6 +/- 1.7% of the dose was excreted as vinylbitaland 11.0 +/- 4.1% as 5-(1'-methylbutyl) barbituric acid, illustrating that also in humans the epoxide-diol pathway plays a role in the metabolism of vinylbital.

Animals↗
PubMed1980

Pharmacokinetics of benzodiazepines. Short-acting versus long-acting.

Among the various benzodiazepines large differences exist with regard to their pharmacokinetic properties and metabolism in man. Some are eliminated from the body at a relatively slow rate (e. g. diazepam), others are metabolized rather rapidly (e. g. oxazepam, temazepam, triazolam). Several benzodiazepines have the long-acting metabolite N-desmethyldiazepam in common (diazepam, fosazepam, prazepam, clorazepate). Such differences may be very important clinically because pharmacokinetic factors will determine the duration of drug effect and pharmacokinetic parameters constitute the basis for a rational dosage regimen. For the various clinical indications of benzodiazepines the required duration of drug action differs quite fundamentally. In anticonvulsant and anti-anxiety treatment continuous treatment is pursued, so that compounds with long elimination half-lives of parent drug or active metabolites are of advantage. If on the other hand a benzodiazepine is taken as a hypnotic, the duration of action should be restricted to the night, hence a compound with a short elimination half-life is to be preferred. A review is given of the pharmacokinetics of the major benzodiazepines presently available.

Anti-Anxiety Agents↗
PubMed1980

The glutathione S-transferases: their role in detoxification and toxification of xenobiotics.

In the first part, the biosynthesis of mercapturic acids is described and attention is payed to the source of the cysteine moiety in those acids, namely glutathione. The second part deals with the present state of knowledge concerning the conjugation of xenobiotics with glutathione, catalyzed by the several several enzymes of the glutathione S-transferase system. The role of the glutathione S-transfereases in the metabolism of xenobiotics is the subject of the third part, emphasizing their functions in detoxification : enzymatical catalysis with glutathione, reversible binding to hydrophobic compounds, and covalent binding to reactive electrophiles. Finally, a recent hypothesis is described with respect to the activation of vicinal dihalogen compounds to reactive agents.

Animals↗
PubMed1979

[Methohexital clearance in patients with acute hepatitis (author's transl)].

Pharmacokinetics of methohexital were studied in patients with acute hepatitis and after a treatment period either with "essential phospholipids" or phenobarbital. During the acute phase the distribution of methohexital was significantly altered. No change had been observed in the methohexital clearance. During remission the distribution of methohexital was in a normal range. After treatment with phenobarbital the methohexital clearance increased significantly whereas no change was observed after treatment with "essential phospholipids".

Acute Disease↗