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  • 1
    Electronic Resource
    Electronic Resource
    Non-linear elimination and protein binding of probenecid (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 395-401 
    Details
    ISSN: 1432-1041
    Keywords: probenecid ; Michaelis-Menten kinetics ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers were given probenecid 0.5, 1 and 2 g p.o. and 0.5 g i.v. The protein binding of probenecid at different concentrations in human plasma was estimated by equilibrium dialysis. The free fraction was found to increase nonlinearly with increasing total probenecid concentration, up to a maximum free fraction of 26%. The plasma concentration-time data after the oral doses were described by a one-compartment open model with first-order absorption and Michaelis-Menten elimination. The mean absorption rate constant 0.0072 min−1 was dose-independent, and the maximal rate of elimination (mean 1429 µg/min) did not differ between doses whether calculated from the total or free concentrations. The Michaelis-Menten constant decreased significantly from 67.1 to 55.5 µg/ml as the dose increased from 1 g to 2 g, while the unbound Michaelis-Menten constant remained unchanged. The elimination of probenecid after the 0.5 g dose was in the linear region of the Michaelis-Menten elimination when calculated from the total and the free concentrations. The volume of distribution increased only slightly from 9.5 to 11.4 l as the dose increased from 0.5 to 2 g, but the unbound volume of distribution decreased significantly from 164 to 99 l. Absorption was complete and was independent of the dose administered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543976
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 197-207 
    Details
    ISSN: 1432-1041
    Keywords: furosemide ; bioavailability ; pharmacokinetics ; oral administration ; i.v. administration ; drug absorption ; moment analysis ; food effect ; dissolution effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 40 mg was administered to 8 healthy subjects as an i.v. bolus dose, as 1 tablet in the fasting state, and as 1 tablet and a solution after food intake. The i.v. data gave a total body clearance of 162±10.8 ml/min and a renal clearance of 117±11.3 ml/min; the volume of distribution at steady state was 8.3±0.61. Oral administration gave a bioavailability of the tablet (fasting) of 51%. Food intake slightly reduced the bioavailability, but not to a significant extent. There was no significant difference in availability between the tablet and the solution. Moment analysis gave a mean residence time after the i.v. dose, MRTi.v., of 51±1.5 min. The mean absorption times (MAT) for all oral doses were significantly longer than the MRTi.v., indicating absorption rate-limited kinetics of furosemide. On average, food delayed the absorption by 60 min. The MAT for the tablet in the postprandial state was significantly longer than for the solution, indicating dissolution rate-limited absorption of the tablet.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630286
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  • 3
    Electronic Resource
    Electronic Resource
    Determinations of 5-hydroxyindoleacetic acid and homovanillic acid in human CSF with monitoring of probenecid levels in CSF and plasma (1987)
    Springer
    Psychopharmacology 92 (1987), S. 144-149 
    Details
    ISSN: 1432-2072
    Keywords: Probenecid ; 5-HIAA ; HVA ; Plasma levels ; CSF ; Humans
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The accumulation of 5-HIAA and HVA in cerebrospinal fluid (CSF) was studied in eight healthy volunteers after oral administration of probenecid. Simulation indicated that a dose of 4.5 g probenecid should be used to achieve probenecid plasma concentrations between 200 and 400 μg/ml. Almost complete inhibition of the active transport of the acidic metabolites was assumed to be obtained at these concentrations. Probenecid 4.5 g was administered in two doses (2.5 g and 2 g), separated by 4 h. Plasma samples were drawn at varying intervals over a period of 46 h and lumbar puncture (LP) was performed at either 14 h or 20 h after the first administration of probenecid. The concentration of probenecid, 5-HIAA and HVA in CSF was estimated and the probenecid-induced accumulation of 5-HIAA and HVA was compared with their baseline values. There were no statistically significant differences (P〉0.05) in the accumulation of the monoamine metabolites between the two LP (14 h and 20 h), neither were there any differences in CSF concentrations of probenecid at the time of LP. There were only small differences in probenecid plasma concentrations, although statistically significant. Due to maximum blockade of the active transport system no correlation was observed between the CSF concentration of probenecid and the induced accumulation of 5-HIAA and HVA, respectively. The range of probenecid-induced accumulation for 5-HIAA and HVA in these volunteers was 156–429% and 183–600%, respectively. The suggested monitoring of probenecid plasma levels is proposed as a suitable model to investigate central neuronal activity of dopamine and serotonin in the central nervous system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00177906
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of haloperidol in psychotic patients (1987)
    Springer
    Psychopharmacology 91 (1987), S. 410-414 
    Details
    ISSN: 1432-2072
    Keywords: Haloperidol ; Pharmacokinetics ; Psychotic patients ; Serum levels ; High performance liquid chromatography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Nine psychotic patients under continuous oral treatment with haloperidol were randomly given a test dose of 1.5–5 mg haloperidol orally and/or intravenously. Serum levels of haloperidol were determined by high performance liquid chromatography and serum concentration data obtained were submitted to pharmacokinetic analysis. The steady state concentration ratio between blood and plasma was determined and found to be 0.79±0.03. The blood clearance was then calculated to be 550±133 ml/min. The mean hepatic extraction ratio was intermediate (0.37). Consequently, for a drug mainly eliminated by hepatic metabolism like haloperidol, the total blood clearance and the extent of oral bioavailability can be affected by changes in hepatic blood flow, hepatic enzyme activities and drug binding. During continuous oral treatment with haloperidol, however, it can be shown that changes in the total metabolic capacity of the liver due to hepatic enzyme induction or inhibition should be important for the therapeutic effects of haloperidol. The volume of distribution at steady state (Vdss) was large (7.9±2.5 l/kg). The terminal half-life was 18.8 h after intravenous and 18.1 h after oral administration. The oral bioavailability (0.60±0.18) were in accordance with previous results in healthy subjects. A mean lag time after oral dose was 1.3±1.1 h and a longer absorption half-life (1.9±1.4 h) was found in the patients compared with healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00216005
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of clonidine in the rat and cat (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 481-494 
    Details
    ISSN: 1573-8744
    Keywords: clonidine ; pharmacokinetics ; blood and brain levels ; liver clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To investigate the pharmacokinetic behavior of clonidine, rats were given clonidine intravenously at 125, 250, and 500μg/kg and blood clonidine concentrations were followed for 6 hr. The disposition of clonidine in two brain regions was studied in rats after an i. v. dose of 500 μg/kg. The liver clearance in rats was investigated by liver perfusion techniques. The results obtained indicate that the disposition characteristics of clonidine can be described by a two-compartment open model in both rats and cats. The penetration of clonidine into tissues is rapid, and brain levels in rats were about 1.7 times higher than blood levels. Brain tissues were found to be an indistinguisible part of the central (blood) compartment. Dose-dependent pharmacokinetic behavior was found for clonidine in rats at the doses used. This was demonstrated by a decrease of both the rate constant of distribution to the peripheral compartment and the overall elimination rate constant from the body, with increase in dose. As a consequence, the volume of distribution and the clearance both decreased with increasing dose. Possible explanations for the dose-dependent behavior of clonidine are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062390
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  • 6
    Electronic Resource
    Electronic Resource
    Multiple receptor responses: A new concept to describe the relationship between pharmacological effects and pharmacokinetics of a drug: Studies on clonidine in the rat and cat (1979)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 495-510 
    Details
    ISSN: 1573-8744
    Keywords: clonidine ; pharmacokinetics ; analgesia ; blood pressure effects ; smooth muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The time course of an observed pharmacological effect is affected not only by the kinetics of the drug levels at the site of action but also by parameters such as the slope and maximum effect of the functional relationship between drug level and response. Using clonidine as a test drug, it was found that the kinetics of its effects on blood pressure and pain responses cannot be described by the time course of clonidine levels in the blood, brain, or the hypothetical tissue compartment of the two-compartment characteristics of this drug. However, the results can be explained assuming that the observed pharmacological effects of a drug are composed of the sum of responses from at least two receptor sites with different slopes and maximal effects. The effect of intravenously administered clonidine on blood pressure in the rat was found to be related to the blood concentrations at least at two receptor sites with opposite effects, one leading to a hypertensive and the other to a hypotensive response. Predictions indicate that a maximum decrease of arterial blood pressure is obtained when the steady-state blood concentration of clonidine is about 1 ng/ml and that no effect is seen at 10 ng/ml. Higher levels will produce an increase of the pressure. The kinetics of the analgesic effect of clonidine in the rat could best be related to the brain levels if the observed effect was considered to be derived from the sum of activity at two receptor sites each producing analgesia. The kinetics of the effects of clonidine on the nictitating membrane of the cat was found to be determined by the kinetics of the drug in the peripheral compartment of the two-compartment open model. Consideration of multiple receptor responses is suggested for future studies on the relationship between the kinetics of drug levels and pharmacological responses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062391
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