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  • 1
    Electronic Resource
    Electronic Resource
    Die Bedeutung der Bindung von Pharmaka an Albumin und Erythrocyten eines Perfusionsmediums der isolierten Rattenleber (1971)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 269 (1971), S. 67-84 
    Details
    ISSN: 1432-1912
    Keywords: Isolated Perfused Rat Liver ; Binding to Erythrocytes ; Binding to Albumin ; Phenothiazine Derivatives ; Bisguanylhydrazone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The binding of lipophilic drugs to albumin and erythrocytes and its importance for the uptake of the drugs into the isolated rat liver were investigated. Promazine and chlorpromazine were taken as lipophilic drugs, which were compared in some experiments with 3,3′-dimethyl-4,4′-diacetyldiphenylbisguanylhydrazone (BG 60), a much more hydrophilic drug. The perfusion medium contained 2% albumin, about 30% bovine erythrocytes and the drug in a concentration of 10−4 M respectively 1.3×l0−4 M in Krebs-Henseleit-solution. In this solution promazine was bound to erythrocytes (69%) and to albumin (20%) whereas the buffer solution contained 11%; 77% of chlorpromazine were bound to erythrocytes, 19% to albumin, whereas the buffer solution contained 4% (Table 1). The distribution of chlorpromazine in the perfusion medium did not depend on the time of incubation (Fig. 1). Increasing the albumin concentration of the perfusion medium caused a rise of the chlorpromazine fraction bound to albumin and a decrease of the fraction bound to the erythrocytes and the fraction of the free, unbound substance (Table 3). The distribution of BG 60 in the perfusion medium markedly depended on the time of incubation. Without incubation 7.5% of BG 60 were bound to erythrocytes, 63% were bound after an incubation time of 2 h (Fig. 1). When suramine was added to the perfusion medium the fraction of promazine bound to albumin increased and the fraction bound to erythrocytes decreased, whereas the fraction of the free substance in the aqueous phase was not significantly changed. In a perfusion medium lacking erythrocytes the fraction of free promazine was considerably higher (Table 1). After the perfusion medium had passed the liver one times, the total chlorpromazine (the fractions of the free and the bound substance) of the first part of the perfusion medium (50 ml) was extracted by the liver (Fig.2). This led to the suggestion that the binding of the phenothiazine derivatives to the membranes of erythrocytes was reversible. In the experiments with BG 60 no fraction of the perfusate of the liver was found, which did not contain BG 60. Beyond that the uptake of BG 60 into the liver depended on the time of incubation of the perfusion medium (Fig. 2). Chlorpromazine was taken up more rapidly than promazine into the recirculating perfused liver (Fig. 3). By suramine the uptake of promazine into the liver was enlarged. KCN did not markedly change the uptake of promazine into the liver (Table 4). If there were no erythrocytes in the perfusion medium the initial uptake of promazine into the liver was increased (Fig.4). There seems to be no difference in the biotransformation of promazine and chlorpromazine as the examination of the perfusate and liver homogenate by thin layer chromatography pointed out. In the experiments with a perfusion medium lacking erythrocytes promazine was much less metabolized (Table 5). The binding of lipophilic substances to erythrocytes may be of similar pharmacokinetic importance as the binding of substances to plasma proteins, as the experiments demonstrated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01422017
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  • 2
    Electronic Resource
    Electronic Resource
    Die Verteilung des Progesteron-3,20-bisguanylhydrazon und des Dodecandion-2,11-bisguanylhydrazon im Meerschweinchenorganismus (1969)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 262 (1969), S. 484-494 
    Details
    ISSN: 1432-1912
    Keywords: Bisguanylhydrazones ; Digitalis-Like Activity ; Guinea Pig Organism ; Distribution ; Binding to Heart Muscle ; Bisguanylhydrazone ; Herzglykosidartige Wirkung ; Verteilung ; Meerschweinchenorganismus ; Haftung am Herzmuskel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Es wurde die Verteilung von Progesteron-3,20-bisguanylhydrazon (BG 31) und von Dodecandion-2,11-bisguanylhydrazon (BG 32) im Meerschweinchenorganismus bestimmt. 0, 3 bzw. 12 Std oder 7 Tage nach einmaliger Infusion der Substanzen wurden bis zu 15 Organe bzw. Körperflüssigkeiten mit einer Indicator-Komplex-Methode auf ihren BG-Gehalt untersucht. Unmittelbar nach Infusion weisen die beiden Substanzen in den verschiedenen Organen eine weitgehend ähnliche Verteilung auf, die mit derjenigen des früher untersuchten 3,3′-Dimethyl-4,4′-diacetyldiphenylbisguanylhydrazon (BG 60) über-einstimmt. Im weiteren Untersuchungszeitraum zeigt BG 31 in mehreren Organen eine dem BG 60 ähnliche lange Verweildauer; diese ist besonders ausgeprägt im Herzen, das nach 7 Tagen die gleiche BG 31-Konzentration wie unmittelbar nach Infusionsende enthält. BG 32 liegt dagegen schon nach 12 Std in fast allen Organen in deutlich verringerter Konzentration vor und ist nach 7 Tagen fast völlig aus dem Organismus verschwunden. Die unterschiedlichen Diketogrundgerüste der drei Bisguanylhydrazone zeigen ihren Einfluß nicht so sehr auf die initiale Verteilung der Substanzen im Organismus, als auf den zeitlichen Konzentrationsverlauf in den einzelnen Organen.
    Notes: Summary The tissue distribution of the digitalis-like substances progesterone-3,20-bisguanylhydrazone (BG 31) and dodecandione-2,11-bisguanylhydrazone (BG 32) was studied in guinea pigs after a single infusion. BG 31 and BG 32 were determined by an indicator-complex-method in 15 different tissues and body fluids immediately after the end of infusion (0 hr) and 3 hr, 12 hr or 7 days later. The distribution of BG 31 and BG 32 did not differ significantly at 0 hr and was similar to the distribution of 3,3′-dimethyl-4,4′-diacetyldiphenylbisguanylhydrazone (BG 60) studied formerly. During the following 7 days BG 31 and BG 60 showed a similar pattern and intensity of binding, whereas BG 32 was eliminated almost completely within this period.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00537845
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  • 3
    Electronic Resource
    Electronic Resource
    Über die subcelluläre Verteilung von 3,3′-Dimethyl-4,4′-diacetyldiphenylbisguanylhydrazon im Meerschweinchenherzen (1969)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 263 (1969), S. 417-426 
    Details
    ISSN: 1432-1912
    Keywords: Bisguanylhydrazone ; Digitalis Like Activity ; Heart Muscle ; Subcellular Distribution ; Guinea Pig ; Bisguanylhydrazon ; herzglykosidartig wirkende Substanz ; Herz ; subcelluläre Verteilung ; Meerschweinchen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Meerschweinchenherzen wurden 0,5—30 min isoliert mit 3,3′-Dimethyl-4,4′-diacetyldiphenylbisguanylhydrazon (BG 60) perfundiert, anschließend homogenisiert und durch Differentialzentrifugation in Kern-Membran-Mitochondrien-, Mikrosomen- und Überstands-Fraktion getrennt. Im Homogenat und in den einzelnen Fraktionen wurde die BG 60-Konzentration und der Proteingehalt bestimmt. Außerdem wurden Herzen von Tieren unmittelbar nach Infusion der Substanz oder 7 Tage danach in gleicher Weise aufgearbeitet. Bei BG 60-Zusatz zum Homogenat lag die höchste auf Protein bezogene Konzentration in der Mitochondrien-Fraktion vor. Der BG 60-Gehalt der Mitochondrien wurde mit zunehmender Perfusionsdauer von demjenigen der Mikrosomen übertroffen. Eine ähnliche Akkumulation von BG 60 in der mikrosomalen Fraktion wurde nach Infusion der Substanz gefunden. Der BG 60-Gehalt der Partikel-Fraktion geht der positiv inotropen Wirkung der Substanz nicht parallel.
    Notes: Summary Isolated guinea pig hearts were perfused with the digitalis like substance 3,3′-dimethyl-4,4′-diacetyldiphenylbisguanylhydrazone (BG 60) for 0.5 to 30 min. The hearts were homogenized and separated by differential centrifugation into nuclear/cell membrane, mitochondrial, microsomal, and supernatant fractions. The hearts of animals given intravenous BG 60 were studied immediately after the end of infusion or 7 days later. The BG 60 and the protein contents of the homogenate and the different fractions were determined. When BG 60 was added to the homogenate, the highest concentration relative to protein content was found in the mitochondria. With increasing time of perfusion the BG 60 concentration of the microsomal fraction exceeded that of the mitochondrial fraction. A similar accumulation of BG 60 in the microsomal fraction was found after the infusion of the substance. The content of BG 60 in the particulate fractions does not parallel the positive inotropic effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00538775
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