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  • 1
    ISSN: 1432-0738
    Keywords: High-pressure-liquid-chromatography ; Bromisoval ; Carbromal ; Methaqualone ; Hochdruckflüssigchromatographie ; Bromisoval ; Carbromal ; Methaqualon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Eine spezifische und empfindliche Methode zur gleichzeitigen Bestimmung von Bromisoval, Carbromal und Methaqualon wird beschrieben. Sie beruht auf der Anlagerung der Substanzen an Aktivkohle bei pH 11 und anschließener Elution von der Aktivkohle mit einem Lösungsmittelgemisch. Die Auftrennung des Eluates erfolgt mittels Hochdruckflüssigchromatographie auf einer Reverse-Phase (RP 18)-Säule. Als mobile Phase dient ein Acetonitril: Wassergemisch (26 ∶ 74). Der Nachweis der eluierten Komponenten erfolgt mittels UV-Absorption bei 210 nm. Die Methode besitzt eine Empfindlichkeit von 0,05 μg Bromisoval und 0,2 μg Carbromal pro ml Serum. Die Repetierbarkeit und Reproduzierbarkeit ist mit Variationskoeffizienten, die in Abhängigkeit von der Konzentration zwischen ± 3,0 und ± 7,6% liegen, als gut anzusehen. Auch die Genauigkeit der Methode ist mit einem Korrelationskoeffizienten von 0,98 für Bromisoval, 0,99 für Carbromal und 0,989 für Methaqualon gut.
    Notes: Abstract A sensitive and specific method for the simultaneous determination of bromisoval, carbromal, and methaqualone is described. The drugs are adsorbed from serum onto charcoal at pH 11 and eluted from it with organic solvent. The eluate is separated by high-pressure liquid-chromatography on reverse phase (RP 18) column using acetonitrile: water (26 ∶ 74 by volume) as mobile phase. The eluted drugs are detected by uv-absorption at 210 nm. The method is sensitive, specific, precise, and accurate.
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  • 2
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Modulators for the reversal of multidrug resistance such as R-verapamil and B8509-035, a dihydropyridine, effectively overcome multidrug resistance in vitro and are currently undergoing clinical trial. One problem with their use is the application protocol; the question as to whether they should be given by continuous administration or in sequential doses in combination with the cytotoxic drugs has to be addressed. Therefore, we examined the influence of the exposure time and the sequence of modulator administration on the active transport of the fluorescent dye rhodamine 123 (R123), a substrate for the P-glycoprotein, in the resistant lymphoblastid cell line VCR1000 and the parental nonresistant cell line CCRFCEM. Our results demonstrate the importance of coadministration of R-verapamil and the cytotoxic agent for the modulation of multidrug resistance, whereas the exposure sequence does not seem to be such an essential parameter in the case of B8509-035. This observation should be considered for the further design of clinical studies.
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  • 3
    ISSN: 1432-0738
    Keywords: Key words Acetylhydrazine ; Isoniazid ; [15N]-Nitrogen ; Laser magnetic resonance spectroscopy ; Cytochrome P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In the pathogenesis of isoniazid-induced hepatic injury, cytochrome P450-dependent metabolic activation of the metabolite, acetylhydrazine (AcHz), is the crucial step. Exhalation of [14C]-carbon dioxide has previously been used to quantify indirectly this pathway. In contrast, according to the current concept of AcHz bioactivation, molecular nitrogen is produced directly, but has not yet been identified. Here, we measured [15N]-nitrogen and 14CO2 exhalation, after the administration of [15N2]-[14C]-AcHz, in rats. Laser magnetic resonance (LMR) spectroscopy, a new sensitive and specific technique for the measurement of 15N and 14N in gas samples, was used. To demonstrate the involvement of cytochrome P450, rats were treated with phenobarbital (PB) or PB + cobalt(II) chloride (CoCl2) (n=3 in each group). Time-dependent 15N2 exhalation differed significantly between treatment groups (p〈0.001). At 240 min, cumulative exhalation of 15N was 1.92±0.43% (mean±SE) of the dose in the control group, 2.53±0.23% in the PB group, and 1.00±0.15% in the PB+CoCl2 group (p〈0.05 compared to controls, p〈0.01 compared to PB). Cumulative exhalation of 14CO2 in 24 h ranged from 15.1 to 21.9%, with no significant difference between treatment groups. In conclusion, N2 is a metabolite of AcHz. N2 formation reflects the cytochrome P450-mediated activation of AcHz and can be used as an index of this pathway. Generally, LMR spectroscopy is valuable for monitoring any N2-liberating process in vivo.
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  • 4
    ISSN: 1432-0843
    Keywords: Key words Cyclophosphamide ; High dose ; Pharmacokinetics ; Application schedule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single 1-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. Patients and methods: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [31P]-nuclear magnetic resonance spectroscopy; [31P]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/m2 infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d1 and d2. Results: (Data are given as mean values for CD and d1/d2 of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d1 of HD, but significantly increased on d2 of HD (CL: 83 and 78/115 ml/min; P 〈 0.01 for d1 versus d2). The latter was translated into an increase in formation CL of both active (+16.4 ml/min) and inactive metabolites (+17.6 ml/min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant decrease was observed in the relative contribution of bioactivation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 22% of the dose (P 〈 0.05 for d1 versus d2 of HD). Conclusions: Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism.
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  • 5
    ISSN: 1432-0843
    Keywords: Key words Cyclophosphamide ; Human lung tissue ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The alkylating cytostatic prodrug cyclophosphamide is bioactivated by the human cytochrome P450 enzyme system. Since these enzymes are not only expressed in human liver, but also in extrahepatic tissue, local bioactivation of this drug may play an important role in its antineoplastic effects, e.g., chemotherapy of lung tumors. This would require uptake of significant amounts of cyclophosphamide into tumor tissue, which has not yet been demonstrated. Methods: We used a recently developed, ex vivo isolated, ventilated and perfused human lung model to study cyclophosphamide uptake into bronchial carcinoma and healthy lung tissue. Following a standard lobectomy, lung samples containing the tumor were perfused with buffer containing 2 mM cyclophosphamide for 2 h. Cyclophosphamide concentrations in perfusate and healthy peripheral tissue were measured during the perfusion and in tumors at the end of perfusion. Results: In all tissue samples, cyclophosphamide uptake was relatively poor, indicated by a tissue to perfusate ratio of 0.021. Moreover, in tumor samples, cyclophosphamide concentrations were significantly lower (P 〈 0.05) than in healthy lung tissue and showed pronounced interindividual variability. Median concentrations were 36.8 μg/g (26.9–44.2 μg/g) in healthy tissue and 5.1 μg/g (0.0–26.8 μg/g) in tumor samples. Tumor cyclophosphamide concentrations varied between 0 and 75% of those reached in healthy tissue. Conclusions: Our results indicate that CP tumor concentrations are modulated by factors different from dose and that expression of bioactivating enzymes in human lung or transfection of genes encoding these enzymes into tumor cells does not necessarily lead to local bioactivation of cyclophosphamide.
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  • 6
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] These conflicting reports could possibly be explained by the limitations of the phenotyping assay used to identify affected FIG. 1 Comparison of nucleotide sequences of DNA encoding functional debrisoquine hydroxylase (dbl) and related cDNAs. The sequence for dbl and variant 'b' are taken ...
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  • 7
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature medicine 7 (2001), S. 285-287 
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] All living organisms, including humans, are continuously exposed to approximately 10,000 chemicals present in food, drinks and the environment. Many naturally occurring compounds are toxic, such as mold aflatoxins, which are among the most potent carcinogens. Various defense mechanisms have evolved ...
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  • 8
    Electronic Resource
    Electronic Resource
    [s.l.] : Nature Publishing Group
    Nature 446 (2007), S. 975-977 
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] ...Safety issues can arise throughout the life-history of a drug — from preclinical screening through to clinical trials and, importantly, after the drug is marketed and tested for the first time on the population at large. Although serious adverse drug reactions (SADRs) that can cause ...
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  • 9
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 5 (1993), S. 414-418 
    ISSN: 0899-0042
    Keywords: gallopamil ; enantiomers ; protein binding ; serum ; α1-acid glycoprotein ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The protein binding of the enantiomers of gallopamil has been investigated in solutions of human serum albumin, α1-acid glycoprotein and serum. Over the range of concentrations attained after oral gallopamil administration, the binding of both enantiomers to albumin, α1-acid glycoprotein, and serum proteins was independent of gallopamil concentration. The binding to both human serum albumin (40 g/liter) [range of fraction bound (fb) R: 0.624 to 0.699; S: 0.502 to 0.605] and α1-acid glycoprotein (0.5 g/liter) (range of fb R: 0.530 to 0.718; S: 0.502 to 0.620) was stereoselective, favoring the (R)-enantiomer (predialysis gallopamil concentrations 2.5 to 10,000 ng/ml). When the enantiomers (predialysis gallopamil concentration 10 ng/ml) were studied separately in drug-free serum samples from six healthy volunteers the fraction of (S)-gallopamil bound (fb: 0.943 ± 0.016) was lower (P 〈 0.05) than that of (R)-gallopamil (fb: 0.960 ± 0.010). The serum protein binding of both (R)- and (S)-gallopamil was unaffected by their optical antipodes (fb R: 0.963 ± 0.011; S: 0.948 ± 0.015) indicating that at therapeutic concentrations a protein binding enantiomer-enantiomer interaction does not occur. The protein binding of (R)- and (S)-gallopamil ex vivo 2 h after single dose oral administration of 50 mg pseudoracemic gallopamil (fb R: 0.960 ± 0.010: predialysis [R] 6.9 to 35.3 ng/ml; S: 0.943 ± 0.016: predialysis [S] 9.5 to 30.7 ng/ml) was comparable to that observed in vitro in drug-free serum. Gallopamil metabolites formed during first-pass following oral administration, therefore, do not influence the protein binding of (R)- or (S)-gallopamil. © 1993 Wiley-Liss, Inc.
    Additional Material: 1 Ill.
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  • 10
    ISSN: 1432-1912
    Keywords: Verapamil ; O-demethylation ; Cytochromes P4502C ; Human liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile]), and verapamil N-demethylation (formation of norverapamil [2,8-bis(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)6-methyl-2-isopropyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (111) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18. In human liver microsomes (n=4), the intrinsic clearance (CLint), as derived from the ratio of V max/Km, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9±1.0 vs 2.4±0.6 ml*min-1 *g-1 mean±SD; p〈0.05), S-Verapamil (16.8±3.3 vs 2.2±1.2 ml* mini*g-1, p〈0.05) and R-verapamil (12.1±2.9 vs 3.6 ±1.3 ml*min-1 * g-1; p〈0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CLint of D-703 formation in human liver microsomes showed a modest but significant degree of stereo selectivity (p〈0.05) with a S/R-ratio of 1.41±0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5±4.5% and 45%, that of D-702 by 52.7±7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703. In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes.
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