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  • 1
    Electronic Resource
    Electronic Resource
    Non-linearities in the pharmacokinetics of di-(2-ethylhexyl) phthalate and metabolites in male rats (1985)
    Springer
    Archives of toxicology 58 (1985), S. 72-77 
    Details
    ISSN: 1432-0738
    Keywords: Diethylhexyl phthalate ; Monoethylhexyl phthalate ; Pharmacokinetics ; Metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The disposition of the plasticizer di-(2-ethylhexyl) phthalate (DEHP) and four of its major metabolites was studied in male rats given single infusions of a DEHP emulsion in doses of 5, 50 or 500 mg DEHP/kg body weight. Plasma concentrations of DEHP and metabolites were followed for 24 h after the start of the infusion. The kinetics of the primary metabolite mono-(2-ethylhexyl) phthalate (MEHP) was studied separately. The concentrations of DEHP in plasma were at all times considerably higher than those of MEHP, and the concentrations of MEHP were much higher than those of the other investigated metabolites. In animals given 500 mg DEHP/kg, the areas under the plasma concentration-time curves (AUCs) of the other investigated metabolites were at most 15% of that of MEHP. Parallel decreases in the plasma concentrations of DEHP, MEHP and the ωand (ω-1) oxidized metabolites indicated that the elimination of DEHP was the rate-limiting step in the disposition of the metabolites. This was partly supported by the observation that the clearance of MEHP was higher than that of DEHP. Nonlinear increases in the AUCs of DEHP and MEHP indicated saturation in the formation as well as the elimination of the potentially toxic metabolite MEHP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00348312
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  • 2
    Electronic Resource
    Electronic Resource
    Determination of clozapine and its N-demethylated metabolite in plasma by use of gas chromatography-mass spectrometry with single ion detection (1988)
    Springer
    Psychopharmacology 95 (1988), S. 472-475 
    Details
    ISSN: 1432-2072
    Keywords: Clozapine ; Mass spectrometry ; Schizophrenia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A gas chromatographic-mass spectrometric method with single ion detection has been developed for determination of clozapine and its N-demethylated metabolite norclozapine in plasma. Propylnorclozapine was used as internal standard and the mass spectrometer was adjusted to record the ion m/z 373 for the compounds analyzed. The precision of the method was found to be high, with a relative standard deviation of 6% or less for replicated samples. The limit of determination was 1.0 ng/ml for clozapine and 5.0 ng/ml norclozapine. A significant correlation was obtained between the daily oral dose of clozapine within the dose interval 100–800 mg/day and the plasma level of clozapine in 22 chronic schizophrenic patients. The plasma levels of clozapine and norclozapine were also significantly correlated. The quotient norclozapine/clozapine showed great interindividual variation and was not correlated to the daily dose of clozapine. The method is rapid and sensitive to allow evaluation of the pharmacokinetic properties of clozapine in the treatment of schizophrenic patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172957
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  • 3
    Electronic Resource
    Electronic Resource
    Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET) (1986)
    Springer
    Psychopharmacology 89 (1986), S. 248-252 
    Details
    ISSN: 1432-2072
    Keywords: Positron emission tomography ; Dopamine receptors ; Clozapine ; N-Methylspiperone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract By means of positron emission tomography the uptake and kinetics of N-(methyl-11C)clozapine in different brain regions have been studied in Rhesus monkeys. 11C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of 11C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for 11C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00310638
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  • 4
    Electronic Resource
    Electronic Resource
    Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 381-395 
    Details
    ISSN: 1573-8744
    Keywords: pethidine ; rat ; physiological flow model ; pharmacokinetics ; pregnancy ; scale up ; opiates, GC-MS analytical method ; simulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The disposition of pethidine (meperidine) in the pregnant rat is described by means of a physiological flow model. The model includes arterial and venous blood, brain, fat, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. The concentration-time profiles of pethidine calculated by the model are consistent with experimental data, except for the brain and renal tissues, where the model predicts initially higher concentrations. Simulations are carried out to further explore the contribution from different organs on the kinetics in blood and tissues. The tissue-to-blood partition coefficients vary over a range from 5 to 316, where fat has the lowest and liver the highest after a correction is made due to hepatic extraction. Rapid uptake occurs into highly perfused organs such as brain, kidneys, liver, and lungs, followed by fetus, intestines, muscle, and fat. Data indicate no marked membrane resistance to pethidine of the investigated organs, except for fetal tissues, but rather a perfusion-limited uptake. Simulations suggest that muscles and adipose tissue play an important role in the rat, becoming the major reservoir of drug during the intermediate and terminal elimination phase, respectively. Volume of distribution and the biological half-life agree with reported findings. Pethidine is subject to a high systemic blood clearance, which exceeds the total hepatic blood flow in the rat. No degradation of pethidine is found in blood, and therefore a pulmonary expression for pethidine clearance is added as a potential source of pethidine elimination. The elimination of pethidine after a single i.v. bolus dose is found to be dependent on simulated changes in cardiac output and hepatic blood flow. A simulation is performed with the scaled model to mimic the human concentration-time profiles in maternal blood and brain tissues and fetal tissue during repetitive doses of pethidine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059198
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  • 5
    Electronic Resource
    Electronic Resource
    Analysis of methadone disposition in the pregnant rat by means of a physiological flow model (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 355-372 
    Details
    ISSN: 1573-8744
    Keywords: methadone ; rat ; pregnancy ; physiological flow model ; pharmacokinetics ; scaleup ; opiates ; GC-MS analytical method
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiological flow model simulating the pregnant rat is constructed for methadone. The model includes brain, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. Since methadone kinetics may provide valuable information for optimal therapy, an attempt is made to describe methadone kinetics in brain and other tissues simultaneously. The concentration-time profiles of methadone in various tissues after an i.v. bolus dose of 2 rng/kg are reasonably described by the model. The role of the different organs in the disposition of methadone is further explored by simulations. It is found that methadone is initially sequestered in lung tissues immediately after intravenous administration. Therefore, both venous and arterial blood pools are included in the model. Rapid uptake then takes place into vascular-rich organs, including kidneys, liver, and muscle, followed by redistribution into less penetrable organs, such as brain, fetal, and intestinal tissues. Data indicate that diffusional resistance governs the transfer of drug into brain, fetal, and intestinal tissues. Simulations suggest that muscular tissues play an important role in the rat and in man, becoming the major methadone reservoir. The tissue-to-blood partition coefficients derived from equilibrium conditions in this study are generally higher than those reported hitherto. The model is scaled up to a human to investigate whether it can be used to predict the concentration of methadone in different organs after a certain dose. Volume of distribution (Vdss) and biological half-life are consistent with earlier findings in man. The study is done by means of the GC-MS method with selected ion-monitoring where deuterated methadone is used as an internal standard.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061474
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  • 6
    Electronic Resource
    Electronic Resource
    Simultaneous determination of ketobemidone and its N-demethylated metabolite in patient plasma samples by gas chromatography mass spectrometry with selected ion monitoring (1983)
    Chichester : Wiley-Blackwell
    Biological Mass Spectrometry 10 (1983), S. 283-286 
    Details
    ISSN: 0306-042X
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: An analytical procedure has been developed for the simultaneous determination of ketobemidone and its N-demethylated metabolite, norketobemidone. After isolation from plasma and re-extraction to acidic aqueous phase, the two aminophenols were extracted as ion pairs with tetrabutylammonium to dichloromethane, where derivatization with ethyl chloroformate took place. Determination was performed by gas chromatography mass spectrometry with selected ion monitoring. Ketobemidone and norketobemidone could be detected in plasma in a concentration of 1 ng ml-1 and 3 ng ml-1, respectively. Determinations were performed down to 5 ng ml-1. The relative standard deviation of the method in the analysis of 10 ng ml-1 of ketobemidone and norketobemidone, respectively, was 8% and 9% (n = 10). The absolute recovery of unconjugated ketobemidone and norketobemidone through the method at the 100 ng ml-1 level was 91% and 85%, respectively. The method was applied to the determination of ketobemidone and norketobemidone in plasma from patients given ketobemidone. The concentrations of unconjugated norketobemidone was too small to be detected.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bms.1200100410
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  • 7
    Electronic Resource
    Electronic Resource
    Investigation of the urinary excretion of pethidine and five of its metabolites in man using selected ion monitoring (1980)
    Chichester : Wiley-Blackwell
    Biological Mass Spectrometry 7 (1980), S. 88-92 
    Details
    ISSN: 1052-9306
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The urinary excretion in man of pethidine and five of its metabolites (norpethidine, pethidinic acid, norpethidinic acid, p-hydroxypethidine and pethidine N-oxide) after a single intramuscular dose has been investigated using analytical procedures based on selected ion monitoring. New methods for the determination of p-hydroxypethidine and pethidine N-oxide have been developed, and the selectivity and sensitivity of the procedures are discussed. Only some 5% of the administered dose was excreted as unchanged pethidine. The mean urinary excretion of norpethidine was 16.4%. Pethidinic acid and norpethidinic acid constituted the major fraction of the dose excreted in urine. The total excretion of pethidinic acid and norpethidinic acid was 41.7 and 23.2%, respectively. Pethidine N-oxide constituted less than 0.5% of the excreted amount, and p-hydroxypethidine could only be detected in the urine of two of the patients. A mean total recovery of about 90% of the dose was found in urine as pethidine and the five metabolites.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bms.1200070210
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