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T Leemann

Publications and source records attributed to T Leemann.

26 records · Page 2Linked to original sources
PubMed1987

[In vitro tests of hepatic oxidation in man, predictive of drug interactions].

Liver monooxygenases are of primary importance in the metabolism of numerous drugs. Their activity, which is genetically controlled, is modulated by environmental factors such as drug treatment. We have developed an in vitro model of human oxidative metabolism in order to evaluate the activity of a specific monooxygenase (debrisoquine type of cytochrome P-450). Substances capable of inhibiting monooxygenase function can be identified and the in vivo occurrence of drug interactions can thus be predicted. - Dextromethorphan O-demethylation in human microsomes prepared from small human liver tissue samples is monitored as the prototype reaction. The kinetic parameters of this reaction are stable and reproducible (Km 1-5 microM, Vmax 9.1 +/- SD 4.6 nmol x mg P-1 x h-1). The reaction is inhibited by numerous drugs (quinidine, phenothiazine type neuroleptics, some dihydropyridines). Preliminary clinical results demonstrate the predictive value of this assay.

Chromatography, High Pressure Liquid↗
PubMed1987

[Evaluation of a caffeine test for determining the phenotype of N-acetyltransferase].

Xenobiotic acetylation by N-acetyltransferase is genetically controlled. This polymorphism governs the intestinal and liver metabolism of numerous amines. The use of caffeine, a ubiquitous and nontoxic amine, has been proposed as a probe for phenotyping. The aim of the present study is to evaluate this test and to identify the metabolite of caffeine used as substrate by the polymorphic enzyme. - A cup of coffee, tea or Coca-Cola is administered to fasting subjects. The molar ratio of two metabolites of caffeine (AFMU and 1X) is determined on a spot urine sample 4-6 hours later by means of a UV liquid chromatographic assay. In a reference population (n = 63), the distribution of molar ratios is trimodal with frequencies of 0.14, 0.35 and 0.51. These results correlate with those obtained by the classic isoniazid test. However, in vitro experiments in human liver subcellular fractions did not lead to the identification of a xanthine as the precursor of the acetylated metabolite.

Acetyltransferases↗
PubMed1986

Stereo- and regioselectivity of hepatic oxidation in man--effect of the debrisoquine/sparteine phenotype on bufuralol hydroxylation.

The influence of the debrisoquine/sparteine-type of oxidation polymorphism on plasma bufuralol concentration and the pattern of urine metabolites was studied in extensive and poor metabolizer subjects. (+)- and (-)-bufuralol, and (+)- and (-)-OH-bufuralol in plasma were determined by enantioselective HPLC, and urinary bufuralol and its metabolites were assayed by gas chromatography-mass spectrometry. Three hours after administration of racemic bufuralol the plasma (-)/(+) isomeric ratio for unchanged bufuralol was 1.84 in extensive metabolizers, indicating preferential clearance of the (+)-isomer through aliphatic 1'-hydroxylation and glucuroconjugation, while the (-)-isomer was mainly eliminated by aromatic 4-hydroxylation. Poor metabolizers were characterized by impaired 1'- and 4-hydroxylation, with almost total abolition of the stereoselectivity of these reactions. The data strongly suggest that both 1'- and 4-hydroxylation are catalyzed by the same enzyme. These in vivo observations are in agreement with recent in vitro data obtained in human liver microsomes from phenotyped patients and support the concept of deficiency of a highly stereoselective cytochrome P-450 isozyme as the cause of this polymorphism.

Adrenergic beta-Antagonists↗
PubMed1986

Interindividual pharmacokinetic and pharmacodynamic variability of different beta blockers.

Hepatic drug metabolism influenced by genetic and environmental factors is a major source of variation in the response to a number of beta-adrenoceptor antagonists. The first study described here was carried out to define the role of a genetic determinant (debrisoquine-type oxidation polymorphism) on plasma concentration of bopindolol and its pharmacological effect. Atenolol was used as a negative and metoprolol as a positive control. In a second study, the relative potency and duration of action of bopindolol were assessed in comparison to atenolol and slow-release oxprenolol. The first study was carried out using 10 healthy volunteers (6 extensive and 4 poor metabolizers), and the second study was carried out using 12 volunteers, all of whom were extensive metabolizers. Genetic polymorphism did not influence the kinetic behavior or pharmacological effects of atenolol. The elimination of bopindolol was slightly but significantly prolonged in poor metabolizers, but this did not significantly alter the cardiac effects of the drug. In the case of metoprolol poor metabolizers showed a significant prolongation of drug elimination, and this was associated with a significant prolongation of the cardiac effects of the drug. The second study revealed that, in terms of cardiac beta-adrenoceptor blockade, 1 mg bopindolol was equipotent to 100 mg atenolol or 160 mg slow-release oxprenolol and that both bopindolol and atenolol had a longer duration of action than slow-release oxprenolol. It is concluded that bopindolol is a potent beta-adrenoceptor antagonist with a very long duration of action which shows little interindividual variability.

Adrenergic beta-Antagonists↗
PubMed1985

Effect of oxidative polymorphism (debrisoquine/sparteine type) on hepatic first-pass metabolism of bufuralol.

Bufuralol is a beta-adrenoceptor blocking drug whose oxidative metabolism is under the same genetic control as debrisoquine and sparteine. The pharmacokinetics of bufuralol were studied in 10 healthy subjects (7 extensive and 3 poor metabolizers of debrisoquine) after oral and intravenous administration. In extensive metabolizers the systemic availability of bufuralol was 43%. Poor metabolizers were characterized by a considerable increase in systemic availability due to a corresponding decrease in hepatic first-pass metabolism. After oral administration of bufuralol non-linear kinetics may occur.

Adrenergic beta-Antagonists↗
PubMed1985

Interindividual variation of beta-adrenoceptor blocking drugs, plasma concentration and effect: influence of genetic status on behaviour of atenolol, bopindolol and metoprolol.

Ten healthy subjects whose genetic oxidative phenotype had been determined (6 extensive and 4 poor metabolizers of the debrisoquine-sparteine type of polymorphism) received single oral doses of 3 beta-blockers: atenolol, bopindolol and metoprolol. The plasma concentrations and the extent of the decrease in exercise-induced tachycardia were determined. The oxidative polymorphism was only significant for substances that had a high hepatic first pass metabolism, such as metoprolol. The metabolic pathway under genetic control was highly stereoselective. This observation must be taken into account when assessing the relation between the plasma concentration and effect of these drugs, which are often administered as racemic mixtures.

Adrenergic beta-Antagonists↗