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  • 1
    ISSN: 1432-1041
    Keywords: Phenylbutazone ; 14C-label ; oxyphenbutazone ; gas chromatography ; disposition ; oxidative metabolism ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption and elimination of orally administered14C-phenylbutazone and the role of oxidation in its metabolism have been studied. The main routes of excretion of14C-phenylbutazone and its metabolites were investigated in 3 patients with rheumatoid arthritis, and in 1 patient with a T-tube in the common bile duct. Up to 9 days after an oral dose of14C-phenylbutazone 600 mg (30 µCi) 63% of the radioactivity was found in the urine and 14% had appeared in the faeces. The cumulative excretion of radioactivity in bile amounted to 9.5% of the dose in 4 days. Only 1% of the radioactivity in the urine and bile was due to unchanged phenylbutazone. The role of oxidative metabolism of phenylbutazone in healthy human subjects was studied by gas chromatography. In 3 subjects given a single dose of phenylbutazone 600 mg, only 8.3% of the dose was excreted in urine as oxidized metabolites after 5 days. However, in 5 patients who had taken phenylbutazone for more than 5 weeks, these metabolites accounted for 23.4% of the dose. These results suggest that oxidative metabolism becomes more important after continued administration of the drug. After a single dose of phenylbutazone, the side-chain oxidized metabolite (II) was the major free derivative excreted in urine, but the ring oxidized metabolite, oxyphenbutazone (I), was much more important than the former in plasma. However, after prolonged treatment there was little difference between the concentration of the two metabolites in plasma. This finding suggests that side-chain oxidation is increased relative to ring oxidation on prolonged treatment with phenylbutazone. A third derivative containing hydroxyl groups both in the phenyl ring and in the side-chain (metabolite III) was found in urine in experiments with phenylbutazone, but in only one out of 3 volunteers given repeated doses of oxyphenbutazone.
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  • 2
    ISSN: 1432-1041
    Keywords: rifampicin ; antipyrine ; 3-hydroxymethylantipyrine ; 4-hydroxyantipyrine ; norphenazone ; cytochrome P-450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Antipyrine is oxidised to three main metabolites in man. There is evidence that the different metabolites are products of different forms of cytochrome P-450. The effect of rifampicin administration for two weeks on the rates of formation of these metabolites was investigated in healthy volunteers. Rifampicin increased antipyrine clearance and shortened its half-life. Two weeks after stopping rifampicin the induction had largely been reversed. Clearance to all three metabolites was increased by rifampicin. Clearance to 3-hydroxymethylantipyrine was increased from 7.8±0.9 ml/min to 13.3±1.3 ml/min, to norphenazone from 5.8±0.6 ml/min to 19.3±2.1 ml/min and to 4-hydroxyantipyrine from 14.3±2.2 ml/min to 21.9±3.9 ml/min. Thus clearance to norphenazone was increased to a much greater extent than to either of the other two metabolites. It is concluded that this provides evidence for the involvement of at least two different forms of cytochrome P-450 in antipyrine metabolism in man.
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  • 3
    ISSN: 1432-1041
    Keywords: liver disease ; environmental factors ; cytochrome P-450 ; NADPH-cytochrome c reductase ; aryl hydrocarbon hydroxylase ; caffeine ; alcohol ; cigarette smoking ; meat consumption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of liver disease and environmental factors on hepatic microsomal cytochrome P-450 content, NADPH-cytochrome c reductase (reductase) activity and aryl hydrocarbon hydroxylase (AHH) activity have been simultaneously investigated in 70 patients undergoing diagnostic liver biopsy. The activity of reductase was not significantly affected by the presence of liver disease or any of the environmental factors studied. Cytochrome P-450 content decreased with increasing severity of liver disease whereas AHH activity was only significantly reduced in biopsies showing hepatocellular destruction. None of the parameters of monooxygenase activity varied significantly with the age or sex of the patients. Alcohol excess was associated with decreased cytochrome P-450 content and AHH activity and this effect was independent of the histological status of the biopsy. Both high caffeine intake and cigarette smoking increased AHH activity in the absence of any change in cytochrome P-450 content. There was a positive correlation between the number of meat meals eaten per week and cytochrome P-450 content. Chronic treatment with enzyme-inducing anticonvulsants appeared to increase both cytochrome P-450 content and AHH activity. Despite differential effects of liver disease and environmental influences on cytochrome P-450 content and AHH activity there was a highly significant correlation between the two parameters. The results of the present study correlate well with the known effects of disease and environment on drug metabolism in vivo.
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  • 4
    ISSN: 1432-1041
    Keywords: Key wordsTerfenadine ; Grapefruit juice ; QT interval
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant administration of grapefruit juice. Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer received 120 mg terfenadine 30 min after drinking 300 ml of either water or freshly squeezed grapefruit juice. The alternative treatment was administered on the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUC), maximum terfenadine concentration (Cmax) and the time to maximum concentration (tmax) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram. Results: Terfenadine was quantifiable in plasma in all 6 subjects on both study days for up to 24 h post-dosing. The AUC of terfenadine was significantly increased by concomitant grapefruit administration (median values 40.6 vs 16.3 ng · ml−1 · h), as was the Cmax (median values 7.2 vs 2.1 ng · ml−1). The tmax was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine levels. The 95% confidence interval for the difference in the change in QTc interval at Cmax was −13 to +38 ms. Conclusion: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability, but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, this does not exclude the risk of cardiotoxicity in high-risk subjects given greater doses of grapefruit juice over longer periods of time.
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  • 5
    ISSN: 1432-1041
    Keywords: Essential hypertension ; clonidine ; plasma levels ; concentration-effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of oral doses of 300 µg of clonidine hydrochloride on blood pressure, sedation and saliva production in 5 essential hypertensives were qualitatively similar to the effects in normotensive subjects. Peak plasma clonidine concentration (1.34±0.28 ng/ml) and plasma half-life (10.0 ±0.8 h) were similar to normotensives. During chronic oral dosing there was no evidence of drug accumulation. Some tolerance to the sedative and salivary flow effects occurred but no tolerance to the hypotensive effect was observed. There was a linear relationship between reduction in saliva flow and plasma levels of clonidine. The hypotensive effect was also related to plasma level at low concentrations. At plasma levels 〉1.5 ng/ml the hypotensive effect was diminished. This loss of effect at high plasma concentration may be related to the peripheral, post-synaptic alpha-adrenoceptor agonist action of the drug.
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  • 6
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 242 (1973), S. 381-382 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] THERE are now 350,000 qualified scientists and engineers (QSEs) in Britain, alongside a population of 550,000 who have reached a similar level of further education outside science. At present, the annual output of 15,000 scientists and 10,000 engineers is showing no sign of increase, and we seem to ...
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  • 8
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1052-9306
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The dimethyl derivatives of clonidine and [2H4]clonidine give good chemical ionization mass spectra when ammonia is used as reagent gas. A gas chromatographic mass spectrometric selected ion monitoring assay for the estimation of clonidine in plasma and urine using ammonia chemical ionization is described.
    Additional Material: 4 Ill.
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  • 10
    Electronic Resource
    Electronic Resource
    Chichester : Wiley-Blackwell
    Biological Mass Spectrometry 7 (1980), S. 183-183 
    ISSN: 1052-9306
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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