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  • pharmacokinetics  (6)
  • Pharmacokinetics  (3)
  • Fibrinolysis  (2)
  • 1
    Electronic Resource
    Electronic Resource
    Bioequivalence of allopurinol preparations: to be assessed by the parent drug or the active metabolite? (1993)
    Springer
    Journal of molecular medicine 71 (1993), S. 240-246 
    Details
    ISSN: 1432-1440
    Keywords: Allopurinol ; Oxipurinol ; Single active metabolite ; First-pass metabolism ; Pharmacokinetics ; Criteria for bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Allopurinol is converted almost completely into a single active metabolite, oxipurinol, which has the same therapeutic pattern but a much longer elimination half-life than the parent compound. Therefore both allopurinol and oxipurinol were evaluated in our bioequivalence study in healthy volunteers comparing two allopurinol brands. Bioequivalence determination was based on the 90% confidence intervals (CI) of the area under the plasma concentration time curve from time zero to infinity (AUC0−∞), of the area from time zero to the last measurable plasma concentration (AUC0−t (last)), and C max. Because of the lack of compound-specific criteria we used conventional limits for the bioequivalence range. Under these conditions the brand chosen as test preparation was judged to be bioequivalent to the reference form with respect to the extent of bioavailability, AUC0−∞, and AUC0−(last) of the parent drug. The CI of C max of allopurinol slightly exceeded the upper limit of 130%, so that bioequivalence was not confirmed with regard to the rate of bioavailability of the parent compound. The CI values of both AUC and C max of the active metabolite were tighter than those of allopurinol. In addition, the CI values of C max of oxipurinol were smaller than those of the corresponding AUC. As a consequence the test drug can clearly be accepted as bioequivalent, based on metabolite data. Since the active metabolite is of greater therapeutic significance than the parent drug, assessment of the bioequivalence of allopurinol preparations needs to be based on oxipurinol rather than allopurinol. Our data provide further evidence that establishing compound-specific criteria is required for bioequivalence evaluation in drugs with a single active metabolite.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00180109
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  • 2
    Electronic Resource
    Electronic Resource
    Benzbromarone hydroxylation in man: defective formation of the 6-hydroxybenzbromarone metabolite (1993)
    Springer
    Journal of molecular medicine 71 (1993), S. 947-952 
    Details
    ISSN: 1432-1440
    Keywords: Benzbromarone metabolism ; Slow elimination phenotypes ; Pharmacokinetics ; Metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To determine the elimination phenotype of the uricosuric agent benzbromarone 100 mg of the drug was administered as a single oral dose to 11 volunteers on a formula diet; plasma concentration-time profiles of the parent drug and the main metabolites M1 (1′-hydroxybenzbromarone) and M2 (6-hydroxy-benzbromarone) were measured by high-performance liquid chromatography for 168 h. Of the 11 subjects 2 showed higher plasma concentrations and delayed elimination of benzbromarone and metabolite M1 but reduced formation of metabolite M2 compared to the other 9 subjects. However, the plasma concentration-time profiles of the metabolites in these two slow eliminators, termed type 2, differed from those of a poor eliminator characterized during a previous study; the latter, termed type 1, eliminated benzbromarone as well as both metabolites M1 and M2 slowly. The differences in the elimination of benzbromarone and its metabolites are probably caused by differences in the activities of the cytochrome P450 mono-oxygenase isozymes. The results show that determination of the phenotype solely by measurement of the 24-h benzbromarone plasma concentration does not unequivocally characterize slow benzbromarone eliminators; additional plasma concentration-time profiles of the parent drug and metabolites are necessary. Metabolite M2 is characterized as 6-hydroxybenzbromarone; the formation and elimination of the chiral metabolite M1 is enantioselective.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00185609
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  • 3
    Electronic Resource
    Electronic Resource
    The effects of a combination of cigarette smoking and oral contraception on coagulation and fibrinolysis in human females (1985)
    Springer
    Journal of molecular medicine 63 (1985), S. 221-224 
    Details
    ISSN: 1432-1440
    Keywords: Smoking ; Oral contraception ; Coagulation ; Fibrinolysis ; Fibrinopeptides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Oral contraception as well as cigarette smoking influence haemostasis. The simulataneous effect of both on blood coagulation and fibrinolysis was studied in nine female smokers. While continuing oral contraception after a 4-week abstinence from smoking the concentration of fibrinogen, antithrombin III and alpha1-Antitrypsin decreased (P〈0.01 orP〈0.04) and of plasminogen increased (P〈0.03). The other coagulation parameters remained unchanged. Although all determinations of these parameters were in the normal range, the observed trends were statistically significant. The concentrations of the fibrinopeptide A and B 15–42 did not differ. It is concluded that the observed alteration is caused by cessation from cigarette smoking.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01731173
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  • 4
    Electronic Resource
    Electronic Resource
    Rapid and slow benzbromarone elimination phenotypes in man: benzbromarone and metabolite profiles (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 577-581 
    Details
    ISSN: 1432-1041
    Keywords: Benzbromarone ; elimination phenotypes ; pharmacokinetics ; metabolism ; genetic variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Following oral administration of the uricosuric drug benzbromarone two major metabolites appear in the circulation, 1'-hydroxy-benzbromarone (M1), and a second product (M2) of unknown structure. The plasma concentrations of the parent drug and of M1 and M2 have now been compared in two different elimination phenotypes, 10 subjects who eliminated the drug rapidly (S1–10) and one individual (S11) whose elimination capacity was impaired, presumably due to genetic variation (S11). The AUC (0–96) of the parent drug in S11 was 145 gmg · ml−1 h, and in the other individuals it averaged 18.3 (11.4–24.5) μg · ml−1 h. The plasma elimination half life of benzbromarone was 3.34 (1.77–5.24) h in the rapid eliminators, and 13.08 h in the subject with the elimination defect. The mean plasma elimination half life of the metabolites in S1–10 amounted to 20.1 (11.9–41.2) h for M1, and 17.2 (12.9–30.7) h for M2. In S11 the plasma elimination half life of M1 was prolonged to 76.6 h, and of M2 to 75.4 h. Thus, the elimination defect in S11 was not restricted to the parent drug, but it also involved the two major metabolites M1 and M2. This might be a consequence of a hepatic enzyme deficiency, or be due to impairment of drug excretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316099
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of sulphinpyrazone and its major metabolites after a single dose and during chronic treatment (1985)
    Springer
    European journal of clinical pharmacology 28 (1985), S. 97-103 
    Details
    ISSN: 1432-1041
    Keywords: sulphinpyrazone ; metabolism ; single dose ; chronic treatment ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulphinpyrazone and its major metabolites (sulfide, sulfone, p-hydroxysulfone and p-hydroxy-sulphinpyrazone) were investigated in 9 volunteers after a single oral dose as well as after chronic treatment for 23 days. Chronic administration of sulphinpyrazone, in comparison with a single oral dose, led to significant changes in plasma AUC (115.86 to 42.90 mg/l·h), in renal clearance (1.06 to 1.80l/h), in hepatic intrinsic clearance (319.0 to 598.0l/h), and in the unbound fraction in plasma 1.15 to 1.69%) and in tissue (2.73 to 1.31%). The volume of distribution changed from 20.24 to 52.041. The steady state concentrations predicted from the single dose were significantly higher than the values found after chronic treatment. The results suggest that sulphinpyrazone induces its own metabolism. The metabolism of the sulfone, p-hydroxysulfone and the p-hydroxy-sulphinpyrazone to further degradation products was also induced. Chronic treatment with sulphinpyrazone reduced the plasma AUC of the sulfide and caused a decrease in its elimination half-life (20.9 to 14.3 h). Since considerable amounts of the sulfide are formed in the G.I. tract, it is suggested that besides the induction of metabolism, bacteria which reduce sulphinpyrazone to the sulfide may also be responsible for the observed pharmacokinetic changes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00635715
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  • 6
    Electronic Resource
    Electronic Resource
    The clinical pharmacokinetics of buflomedil in normal subjects after intravenous and oral administration (1981)
    Springer
    European journal of clinical pharmacology 20 (1981), S. 459-463 
    Details
    ISSN: 1432-1041
    Keywords: buflomedil ; vasodilatation ; pharmacokinetics ; bioavailability ; vasoactive drug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A dose-ranging pharmacokinetic study of buflomedil was carried out in eight subjects to determine the pharmacokinetic parameters of the drug after oral and intravenous administration. Based on AUC∞ analyses, the pharmacokinetics of buflomedil were found to be linear within the dose ranges studied (50 to 200 mg for i. v. injection and 150 to 450 mg for oral administration). In the oral study, the mean biological half-life of the drug was 2.97 h, while after intravenous dose it was 3.25 h. The apparent volume of distribution after the pseudodistribution equilibrium (Fdβ) and volume of distribution at the steady state (Vdss) were 1.43±0.24 l/kg and 1.32±0.26 l/kg, respectively. The mean urinary recovery of intact drug and the metabolite, paradesmethyl buflomedil, after intravenous dosing, were 23.6% and 18.7%, respectively, while after oral dosing, they were 18% and 14.8%, respectively. On the average, 72% of the dose was obserbed into the systemic circulation after oral administration. This level of bioavailability was attributed to the hepatic first-pass effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542100
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  • 7
    Electronic Resource
    Electronic Resource
    Correlation between the pharmacokinetics and pharmacodynamics of dopamine in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 163-169 
    Details
    ISSN: 1432-1041
    Keywords: dopamine ; pharmacokinetics ; pharmacodynamics ; adrenaline plasma level ; noradrenaline plasma level ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and the pharmacodynamic action of dopamine were investigated in 5 healthy subjects. Dopamine was given in different doses (200, 400 and 800 µg/min) by constant intravenous infusion over 90 min. In order to control the influence of the procedure on the measured parameters the subjects also received a similar infusion of saline. Dopamine, noradrenaline and adrenaline levels in plasma were followed for up to 6 h after the infusion, and arterial pressure and heart rate were monitored. Dopamine reached a steady state level within 15 to 30 min after commencement of the infusion; the steady state levels averaged 36.5 µg/l at 200 µg/min, 73.8 µg/l at 400 µg/min and 207 µg/l at 800 µg/min. The corresponding total clearances were 5.8 l/ min, 5.51/min and 3.9 l/min suggesting non-linear kinetics. The kinetics could not be described by compartmental model. Noradrenaline and adrenaline levels were found to be elevated during infusion of dopamine. Noradrenaline had returned to its pretreatment level within 15 to 30 min after cessation of the infusion, whereas the adrenaline level did not return to the pretreatment value within the observation period. Heart rate was increased by the dose of 400 µg/min, and the systolic and mean arterial pressures were elevated, whereas distolic blood pressure remained unchanged. Elevated systolic blood pressure was better correlated with plasma dopamine than with noradrenaline concentration. This finding, in conjunction with the unchanged diastolic blood pressure, indicates that elevation of the systolic blood pressure is a direct rather than an indirect effect of dopamine. The increased heart rate was not correlated with the dopamine level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630281
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  • 8
    Electronic Resource
    Electronic Resource
    Lack of clinically important interaction between erythromycin and theophylline (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; erythromycin ; interaction ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 11 healthy volunteers the kinetics of theophylline and the plasma levels and the urinary excretion of its metabolites were studied before and after treatment with erythromycin for 10 days. Theophylline was administered as an intravenous bolus injection (280 mg) followed by a constant intravenous infusion (23.8±4.1 mg/h) for 6 hours. The total clearance of theophylline at steady-state (63.4±9.9 vs 63.8±14.4 ml/min, before vs after erythromycin treatment) and the elimination half-life after cessation of the infusion (6.7±2.6 vs 7.5±1.8 h, before vs after treatment) did not change during the treatment with erythromycin. No difference in the formation of metabolites before and after treatment with erythromycin was detected; the findings in urine were 40.4±5.0 vs 42.1±5.4% 1,3-dimethyluric acid, 29.6±4.6 vs 30.1±5.9% 1-methyluric acid and 13.4±3.5 vs 12.5±2.2% 3-methylxanthine before and after erythromycin treatment, respectively. It is concluded that a clinically relevant interaction between erythromycin and theophylline does not occur.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542146
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  • 9
    Electronic Resource
    Electronic Resource
    Plasma and urinary levels of triamterene and certain metabolites after oral administration to man (1979)
    Springer
    European journal of clinical pharmacology 16 (1979), S. 39-44 
    Details
    ISSN: 1432-1041
    Keywords: triamterene ; pharmacokinetics ; diuretic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma and urinary levels of triamterene and two metabolites were measured using a specific method of analysis. Urinary excretion was completed after 48 h, which permitted a rough estimate of its half-life as longer than two hours. The areas under the curve were 672.5±160.3 and 1.311.3±399.1 µg/ml × h after the triameterene 150 mg and 300 mg p.o., respectively and correspondingly 4.2±1.4% and 3.7±0.6% of the dose were excreted as unchanged drug. The principal metabolite of triamterene found was the sulfate conjugate. The area under the curve of this metabolite amounted to 6.672±2.120 and 11.941±5.005 µg/ml × h after the of 150 mg and 300 mg triamterene doses, respectively. The urinary excretion of the metabolite varied between 25.0±4.0% and 17.5±3.5% of the dose after either dose. In healthy subjects an effect on sodium excretion was observed after a dose of 150 mg, whereas the potassium-retaining effect was observed only after the dose of 300 mg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00644964
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  • 10
    Electronic Resource
    Electronic Resource
    Die intraindividuelle Streuung der fibrinolytischen Aktivität bei Probanden (1978)
    Springer
    Journal of molecular medicine 56 (1978), S. 445-448 
    Details
    ISSN: 1432-1440
    Keywords: Fibrinolysis ; Circadian rhythms ; Clinical trial ; Euglobulinlysis-time ; Fibrinolyse ; circadiane Rhythmik ; klinische Prüfung ; Euglobulinlyse-Zeit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Bei 5 Probanden wurde über einen Zeitraum von 6 Wochen fünfmal die Anstiegsphase im Tagesrhythmus der fibrinolytischen Aktivität untersucht. Als Parameter wurden die Euglobulinlyse-Zeit und die Papierfibrinolyse, die Plasmaproteine, Fibrinogen, Plasminogen, α1-Antitrypsin und α2-Makroglobulin sowie die Thrombinocoagulase-Zeit und die Fibrinspaltprodukte erfaßt. Es zeigte sich bei allen Probanden der Anstieg der Fibrinolyse am Vormittag. Die Schwankungsbreite der fibrinolytischen Aktivität ist intraindividuell kleiner als bei einem interindividuellen Vergleich. Weiterhin zeigt sie mittags eine geringere Streuung als vormittags. Bei Untersuchungen zur klinischen Prüfung eines Soforteffektes von Arzneimitteln auf die Fibrinolyse sollte der Zeitraum der Plateauphase der fibrinolytischen Aktivität gewählt werden, um die Streuung der Ausgangswerte möglichst gering zu halten. Weiterhin ist die intraindividuelle Streuung der fibrinolytischen Aktivität in diesem Zeitraum geringer als während der Anstiegsphase im Rahmen des circadianen Rhythmus der Fibrinolyse. Eine intraindividuelle Kontrolle muß gewährleistet werden.
    Notes: Summary In five volunteers fibrinolytic activity has been measured five times over a period of six weeks during increasing values of circadian rhythm. Euglobulinlysis-time, paper fibrinolysis, fibrinogen, plasminogen, α1-antitrypsin, α2-makroglobulin, thrombinocoagulase-time and fibrin-split-products were used in one study. An increase of fibrinolytic activity in the mooning was observed in all volunteers. Intraindividual variation of values is considerable but less than variation of values compared interindividually. Moreover variation was smaller at noon than in the time before noon. In clinical trial of the short-time effect of drugs the period of the plateau of the fibrinolytic activity should be used because of its smaller variation of values. Furthermore, in this period the intraindividual variation of the fibrinolytic activity is smaller than during increasing slope of the circadian rhythm of fibrinolysis. Intraindividual control should be granted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01477058
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