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  • 1
    Electronic Resource
    Electronic Resource
    Radioimmunoassay of propranolol (1983)
    s.l. : American Chemical Society
    Analytical chemistry 55 (1983), S. 1572-1575 
    Details
    ISSN: 1520-6882
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/ac00260a028
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  • 2
    Electronic Resource
    Electronic Resource
    Comparative in vitro cytotoxic effects of taxol and its major human metabolite 6α-hydroxytaxol (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 129-135 
    Details
    ISSN: 1432-0843
    Keywords: Key words Taxol ; 6α-Hydroxytaxol ; HL-60 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Taxol is metabolized by the liver microsomal cytochrome P450 enzyme system into its principal metabolite 6α-hydroxytaxol (6HT). In the present in vitro studies 6HT was compared to taxol with respect to its effects on tubulin depolymerization, mitotic arrest, clonogenic survival and apoptosis in HL-60 cells. 6HT was generated by incubating taxol with human liver microsomes in a NADPH-generating system. HL-60 cells were incubated for 24 h with either taxol or 6HT, washed and placed in drug-free suspension or cultured for colony growth in agarose. For the suspension and colony culture growth of the cells, the IC50 concentrations of 6HT were 500±46 and 350±37 nM, while those of taxol were 3.2±0.2 and 2.8±0.5 nM, respectively. Immediately after a 24-h exposure of HL-60 cells to 50 nM taxol, electrophoresis of genomic DNA from HL-60 cells revealed an internucleosomal DNA fragmentation ′ladder′. In addition, 39% of the cells were arrested in mitosis and 16% showed the morphologic features of apoptosis. In contrast, an identical treatment with 6HT resulted in the mitotic arrest of only 2.8% of the cells, with 4.0% displaying apoptosis (P〈0.01); internucleosomal DNA fragmentation was not observed. 6HT was also significantly less effective than taxol in inhibiting the temperature-induced depolymerization of microtubules in a cell-free system. However, at equipotent concentrations, the effect of 6HT on tubulin depolymerization, mitotic arrest or apoptosis was similar to that of taxol. In addition, at concentrations of taxol or 6HT at or below their IC50, there was little tubulin depolymerization, mitotic arrest or apoptosis. The results presented here show that the biotransformation of taxol to 6HT substantially detoxifies taxol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689197
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  • 3
    Electronic Resource
    Electronic Resource
    Extensive and saturable accumulation of paclitaxel by the human platelet (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 41-44 
    Details
    ISSN: 1432-0843
    Keywords: Taxol ; Paclitaxel ; Platelets
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Little is known about the cellular distribution of paclitaxel in humans. In the present study we examined the distribution of [3H]-paclitaxel in human blood. When 1 μM paclitaxel was incubated with fresh blood at 37°C, the platelet/plasma concentration ratio was 240±17 (mean±SEM), whereas the red blood cell (RBC)/plasma concentration ratio was only 0.59±0.05. In kinetics experiments using platelet-rich plasma, we observed that the platelet accumulation of paclitaxel was highly temperature- and concentration-dependent. Scatchard analysis of the 37°C uptake data demonstrated a dissociation constant (K app) of 0.80±0.10 μM and a maximal binding capacity of 672±102 pmol/109 platelets. It is proposed that the platelet accumulation of paclitaxel reflects binding to microtubules and may serve as a useful model for binding to less accessible cellular sites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685730
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  • 4
    Electronic Resource
    Electronic Resource
    Comparative in vitro cytotoxic effects of taxol and its major human metabolite 6α-hydroxytaxol (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 129-135 
    Details
    ISSN: 1432-0843
    Keywords: Taxol ; 6α-Hydroxytaxol ; HL-60 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Taxol is metabolized by the liver microsomal cytochrome P450 enzyme system into its principal metabolite 6α-hydroxytaxol (6HT). In the present in vitro studies 6HT was compared to taxol with respect to its effects on tubulin depolymerization, mitotic arrest, clonogenic survival and apoptosis in HL-60 cells. 6HT was generated by incubating taxol with human liver microsomes in a NADPH-generating system. HL-60 cells were incubated for 24 h with either taxol or 6HT, washed and placed in drug-free suspension or cultured for colony growth in agarose. For the suspension and colony culture growth of the cells, the IC50 concentrations of 6HT were 500±46 and 350±37 nM, while those of taxol were 3.2±0.2 and 2.8±0.5 nM, respectively. Immediately after a 24-h exposure of HL-60 cells to 50 nM taxol, electrophoresis of genomic DNA from HL-60 cells revealed an internucleosomal DNA fragmentation ‘ladder’. In addition, 39% of the cells were arrested in mitosis and 16% showed the morphologic features of apoptosis. In contrast, an identical treatment with 6HT resulted in the mitotic arrest of only 2.8% of the cells, with 4.0% displaying apoptosis (P〈0.01); internucleosomal DNA fragmentation was not observed. 6HT was also significantly less effective than taxol in inhibiting the temperature-induced depolymerization of microtubules in a cell-free system. However, at equipotent concentrations, the effect of 6HT on tubulin depolymerization, mitotic arrest or apoptosis was similar to that of taxol. In addition, at concentrations of taxol or 6HT at or below their IC50, there was little tubulin depolymerization, mitotic arrest or apoptosis. The results presented here show that the biotransformation of taxol to 6HT substantially detoxifies taxol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689197
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  • 5
    Electronic Resource
    Electronic Resource
    Induction of UDP-Glucuronosyl-Transferase by the Flavonoids Chrysin and Quercetin in Caco-2 Cells (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 21-26 
    Details
    ISSN: 1573-904X
    Keywords: flavonoids ; chrysin ; quercetin ; induction ; glucuronidation ; UDP-glucuronosyltransferase ; Caco-2 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Dietary flavonoids have been reported to be potent inhibitorsof drug metabolizing enzymes. In the present study we examined theinducing effect of three of these compounds, chrysin, quercetin andgenistein, on UDP-glucuronosyltransferase (UGT) in the humanintestinal cell line Caco-2. Methods. The induction of UGT by flavonoid pretreatment was studiedboth in the intact cells and cell homogenates, measured as theglucuronidation of chrysin, and by immunoblot analysis of the UGT 1A protein. Results. Exposure of Caco-2 cells to 50 μM chrysin resulted in a3.8-fold increase in chrysin glucuronidation in intact cells (p 〈 0.0001)with a 38% decrease in sulfation (p 〈 0.01). In the cell homogenatethe induction was much larger, 14-fold. The induction was slow todevelop with maximum induction after 3–4 days. Interestingly, theisoflavonoid genistein was without effect. Immunoblot analysis ofCaco-2 cell microsomes with a UGT1A subfamily-selective antibodyshowed a markedly increased band at about 59 kDa, consistent withinduction of one or more UGT1A isoforms. A 5-week exposure ofCaco-2 cells to low concentrations (10 μM) of chrysin or quercetinalso showed markedly increased glucuronidation activity. Conclusions. Diet-mediated induction of intestinal UGT may beimportant for the bioavailability of carcinogens and other toxicchemicals as well as therapeutic drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007506222436
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  • 6
    Electronic Resource
    Electronic Resource
    Stereochemistry of tissue distribution of racemic propranolol in the dog (1989)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 1 (1989), S. 192-196 
    Details
    ISSN: 0899-0042
    Keywords: propranolol enantiomers ; enantiomers ; propranolol ; β-receptor-blocking drugs ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Only limited information is available on the stereochemistry of the in vivo distribution of β-receptor-blocking drugs. In this study we determined the levels of the propranolol enantiomers in plasma, cerebrospinal fluid (CSF) and central nervous system (CNS), and peripheral tissues in the dog following an intravenous dose of a deuterium-labeled pseudoracemate. The appearance of the propranolol enantiomers in the CSF was rapid and nonstereoselective, with maximum concentrations reached at 15 min after dosing. The levels of the enantiomers in both CSF and plasma then declined in a parallel biphasic fashion, with a terminal t1/2 of about 125 min. Except for an early high CSF/plasma concentration ratio of 0.35, the CSF propranolol levels corresponded to the unbound concentration in plasma, CSF/plasma 0.20. All areas of the brain showed a similar uptake of propranolol, with a tissue concentration exceeding that in plasma about 10-fold during the terminal phase of elimination. The uptake of propranolol by peripheral tissues varied widely, ranging from a 50-fold accumulation by the lungs compared to plasma to no accumulation by adipose tissue. However, as for the CSF, there was no evidence of stereoselective uptake of propranolol by any CNS or peripheral tissue except for the liver. A significantly higher level of (+)- vs. (-)-propranolol in liver tissue presumably was a reflection of stereoselective hepatic metabolism of (-)-propranolol by this tissue. The slight stereoselectivity in plasma binding of propranolol known to exist in the dog had no significant influence on tissue or CSF distribution.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530010303
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  • 7
    Electronic Resource
    Electronic Resource
    Enantioselective sulfation of β2-receptor agonists by the human intestine and the recombinant M-form phenolsulfotransferase (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 10 (1998), S. 800-803 
    Details
    ISSN: 0899-0042
    Keywords: β2-agonist drugs ; sulfotransferase ; M-form phenolsulfotransferase ; sulfation ; isoproterenol ; metaproterenol ; terbutaline ; albuterol ; salbutamol ; salmeterol ; formoterol ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The β2-receptor agonist class of drugs is metabolized in humans almost exclusively by sulfate conjugation. The objective of this investigation was to determine the influence of chemical structure on the stereoselectivity of the sulfoconjugation of these chiral drugs. The pure enantiomers of six β2-agonists, including those clinically most widely used, were all effectively sulfated both by the cytosol of the human intestine and the recombinant human M-form phenolsulfotransferase (PST). Whereas the apparent Km values (Km,app) for the sulfation of the individual drug enantiomers by the intestinal cytosol varied widely, ranging from 4.8 μM for (S)-isoproterenol to 889 μM for (S)-albuterol, these Km,app values were highly correlated with those obtained with M-PST (correlation coefficient 0.994). In contrast, the M-PST Vmax,app values were similar for all drug enantiomers, ranging from 276 to 914 pmol min-1 mg-1 protein, implying that substrate binding to M-PST by far is the main determinant of the sulfation activity. For isoproterenol, the Km,app for M-PST was 6.1 times higher for the active (R)- than for the inactive (S)-enantiomer. For other β2-agonists, the stereoselectivity decreased towards unity as the Km,app increased. However, for albuterol, containing a hydroxymethyl substituent at the aromatic ring, the stereoselectivity was dramatically reversed, with 10 times higher Km,app for the inactive (S)- than for the active (R)-enantiomer. Chirality 10:800-803, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Stereoselective sulfate conjugation of isoproterenol in humans: Comparison of hepatic, intestinal, and platelet activity (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 5 (1993), S. 602-609 
    Details
    ISSN: 0899-0042
    Keywords: phenol sulfotransferase ; β-agonist ; drug enantiomers ; stereospecific ; chiral ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The stereochemistry of sulfate conjugation of isoproterenol (ISO) was examined with human liver, intestine, and platelets as the phenolsulfotransferase (PST) enzyme source and PAP35S as the cosubstrate. With the hepatic cytosol, two distinct sulfation reactions were identified, a high affinity reaction (Km 5 to 50 μM) and a low affinity reaction (Km 360 to 2,900 μM). The efficiency of sulfation (Vmax/Km) for both reactions was 5-fold higher for (+)- than for (-)-ISO. When the hepatic PSTs were resolved by ionexchange chromatography, it could be shown that the high affinity reaction was catalyzed by the monoamine (M) form and the low affinity reaction by the phenol (P) form of PST. Only the high affinity (M form) sulfation was detected in the jejunal cytosol with a Vmax/Km value 6.1-fold higher for (+)- than for (-)-ISO. Finally the platelet, as a potentially useful model tissue, also demonstrated only the high affinity M form reaction with a Vmax/Km value 5.7-fold higher for (+)- than for (-)-ISO. In summary, this study has shown that sulfation of ISO by PSTs in various human tissues is stereoselective and favors the inactive (+)-enantiomer over the active (-)-enantiomer by about 5-fold, a finding which should be considered in the therapeutic use of chiral drugs cleared by sulfate conjugation. © 1993 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530050807
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  • 9
    Electronic Resource
    Electronic Resource
    Stereoselective sulfation of terbutaline by the rat liver cytosol: evaluation of experimental approaches (1989)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 1 (1989), S. 121-126 
    Details
    ISSN: 0899-0042
    Keywords: stereoselective metabolism ; sulfate conjugation ; in vitro sulfation ; sympathomimetic amines ; chiral separation ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Little is known about the stereochemistry of sulfation of chiral phenolic drugs. In this study we examined several in vitro approaches to this question, using (+)-, (-)-, or (±)-terbutaline as the substrate and the rat liver cytosol as the phenolsulfotransferase enzyme source. The cosubstrate PAPS was either generated by the cytosol from inorganic sulfate and ATP or added to the cytosol. The intact sulfate conjugates formed were determined by HPLC. Using the PAPS generating system, which is best suited for the production of relatively large quantities of sulfate conjugates, with the individual enantiomers as substrates, (+)-terbutaline was conjugated to a much greater extent than (-)-terbutaline; the (+)/(-)-enantiomer ratio was 7.3 ± 0.3 (mean ± SE). When (±)-terbutaline was the substrate and chiral derivatization was employed to separate the sulfate enantiomers formed, a similar (+)/(-)-enantiomer ratio of 7.9 ± 0.2 was obtained. With PAP35S added to the cytosol, an approach best suited for kinetic studies, the substrate concentration dependence of sulfation could be determined. The Km app for this reaction was identical for (+)- and (-)-terbutaline. However, the Vmax app was 8.1 ± 0.4 times greater for (+)-terbutaline. This study for the first time shows enantioselectivity in sulfation of a chiral phenolic drug. The experimental approaches used should be valuable for human studies of stereoselectiven sulfation of terbutaline and other chiral drugs.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530010205
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  • 10
    Electronic Resource
    Electronic Resource
    Influence of food on the intravenous and oral dose kinetics of propranolol in the dog (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 229-241 
    Details
    ISSN: 1573-8744
    Keywords: food effects ; propranolol ; kinetics ; dogs ; oral and intravenous doses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The intravenous and oral dose kinetics of propranolol were studied in the dog both in a fasted state and immediately after a meal consisting of 100 g of cooked beef liver. Fifty ΜCi of3H-propranolol was administered intravenously simultaneously with a 40-mg oral dose of unlabeled propranolol. Plasma3H-propranolol was measured by specific extraction and liquid scintillation spectrometry, and unlabeled plasma propranolol was determined by gas chromatography-mass spectrometry. Feeding significantly reduced (25%) the elimination half-life and increased (52%) the systemic clearance of intravenous propranolol. The increase in the systemic clearance of propranolol after feeding was mostly due to an increase (60%) in apparent hepatic blood flow, which appeared to remain elevated for 5–7 hr. The meal had no influence on the apparent volume of distribution or plasma binding. Feeding did not affect the area under the concentration-time curve of oral propranolol, but significantly delayed the rate of oral propranolol absorption, shifting the time to reach peak plasma levels from 60 to 158 min. The results of this study suggest that feeding alters the disposition of propranolol in the dog by producing a sustained increase in hepatic blood flow.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01065654
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