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  • 1
    ISSN: 1432-0843
    Keywords: Key words Trofosfamide ; Ifosfamide ; Cyclophosphamide ; Oral chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m2 Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUCTrofo:AUCIfo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUCIfo:AUCCyclo 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechloroethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy.
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  • 2
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Journal of the American Chemical Society 94 (1972), S. 1276-1282 
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 0899-0042
    Keywords: thalidomide enantiomers ; HPLC ; hydroxylated metabolites ; mass spectrometry ; EM 12 ; in vitro metabolism ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The stereoselective metabolism of the former sedative thalidomide and the metabolism of its analogue EM 12 were studied in vitro with liver homogenates. In our study we focused on hydroxylated nonhydrolyzed metabolites of thalidomide. An analytical HPLC method was developed to determine these metabolites directly. The investigations showed a highly stereoselective biotransformation of thalidomide. 5-Hydroxy thalidomide was preferentially formed by (-)-(S)-thalidomide, whereas (+)-(R)-thalidomide was metabolized to two hitherto unknown compounds (Met A and B). Mass spectrometry of these metabolites Met A and B indicated that oxidation or hydroxylation took place in the glutarimide moiety. Biotransformation studies with the more stable thalidomide analogue EM 12 revealed four new metabolites (Met C—F) whose quantities differed in the selected liver homogenate. © 1994 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
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  • 5
    ISSN: 0899-0042
    Keywords: zopiclone ; chiral liquid chromatography ; enantioseparation ; fractional crystallization ; cyclopyrrolone ; benzodiazepine receptor binding ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We report the preparative separation of rac-zopiclone using malic acid as the resolving agent. Furthermore, two different methods for the analytical determination of zopiclone enantiomers by HPLC on chiral stationary phases are described. The benzodiazepine receptor binding of the isolated enantiomers was investigated. Half-maximal inhibitory concentrations of (+)- and (-)-zopiclone were 21 or 1,130 nmol/liter, respectively, indicating a more than 50 times higher affinity of the (+)-enantiomer toward the receptor. © 1993 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
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  • 6
    ISSN: 0899-0042
    Keywords: configurational stability ; pH ; temperature ; ionic strength ; phosphate buffer concentration ; plasma protein affinity ; native cyclodextrins ; cyclodextrin derivatives ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The configurational stability of (+)- and (-)-diethylpropion [(+)- and (-)-2-(diethyl)-1-phenyl-1-propanone or (+)- and (-)-DEP] was investigated systematically from chemical, pharmaceutical, and pharmacological aspects. The enantiomeric ratio was monitored directly with a recently developed stability-indicating enantioselective HPLC method.In aqueous solutions, the rate of racemization increased non-linearly with increasing pH and with increasing phosphate buffer concentration. The racemization rate showed a positive slope with increasing temperature and decreasing ionic strength.The racemization rates of (+)- and (-)-DEP in the presence of cyclodextrins (CDs) did not differ significantly. CDs that were added to (+)- and (-)-DEP in a molar ratio 5:1 showed the following effects after dissolution in 10 mM phosphate buffer (final pH 6.7): sulfobutyl ether-β-CD (SBE-β-CD) and methylated-β-CD (Me-β-CD) retarded racemization; whereas hydroxypropyl-β-CD (HP-β-CD), acetyl-γ-CD (Ac-γ-CD), acetyl-β-CD (Ac-β-CD), γ-CD, and β-CD showed a weak destabilising effect. In contrast to the described CDs, α-CD distinctly accelerated the rate of racemization.The configurational stability of (+)- and (-)-DEP was also studied under physiological conditions. The half-life of racemization in heparinised human plasma was for both enantiomers determined to be approximately 23-25 min.In phosphate buffer (10 mM, pH 7.4), rac-DEP showed a high, but unselective affinity towards human α1-acid glycoprotein (orosomucoid) immobilised on silica (Chiral AGP).The rate of racemization of the free base of (-)-DEP dissolved in organic solutions generally increases with the polarity of the solvating agent. Chirality 10:307-315, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
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  • 7
    ISSN: 1432-0843
    Keywords: Key words Trofosfamide ; Ifosfamide ; Cyclophosphamide ; Metabolism ; Cytochrome P450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Trofosfamide and its congeners ifosfamide and cyclophosphamide are cell-cycle-nonspecific alkylating agents that undergo bioactivation catalyzed by liver cytochrome P450 (CYP) enzymes. Two NADPH-dependent metabolic routes for the anticancer drug trofosfamide, i.e., 4-hydroxylation and N-dechloroethylation, were studied in human liver microsomes and in seven recombinant human CYP isoforms (i.e., CYP1A1, 1A2, 2A6, 2B6, 2D6, 2E1, and 3A4-OR) to identify the CYP enzymes involved. Recombinant human CYP3A4 and CYP2B6 exhibited catalytic activity with respect to both pathways of trofosfamide. Enzyme kinetic analyses revealed the dominant role of human CYP3A4 in 4-hydroxylation and N-dechloroethylation of trofosfamide. This was confirmed by the observation that only the CYP3A4 contents of five samples of human liver microsomes correlated with both pathways of trofosfamide. Furthermore, ketoconazole, a selective inhibitor of CYP3A4, substantially inhibited microsomal trofosfamide 4-hydroxylation and N-dechloroethylation (50% inhibitory concentration 〈 1μM for both reactions). The present study indicates that human liver microsomal CYP3A4 preferentially catalyzes the two NADPH- dependent metabolic routes of trofosfamide, which emphasizes the necessity for awareness of potential interactions with any coadministered drugs that are CYP3A4 substrates.
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  • 8
    Electronic Resource
    Electronic Resource
    Weinheim : Wiley-Blackwell
    ISSN: 0570-0833
    Keywords: Chiral resolution ; Analytical methods ; Chromatography ; Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A number of racemates can be resolved into optically pure enantiomers by chromatography on optically active adsorbents. Synthetic polymers with optically active amide, amino acid, and crown ether groups, natural products such as starch and cellulose, and also microcrystalline triacetylcellulose are suitable for this purpose. Racemates can also be resolved by gas chromatography on optically active stationary phases.
    Additional Material: 5 Ill.
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  • 9
    ISSN: 1432-1955
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract In the present study, the effects of the enantiomers of the anthelmintic drug praziquantel (PZQ) and its main metabolitetrans-4-hydroxypraziquantel (TRANS) on pairs ofSchistosoma mansoni worms were examined in vitro. Highly purified enantiomers (optical purity, 〉99.9% for PZQ and 99.0% for TRANS) were used. Paired worms were incubated for 4 h in RPMI medium containing 0.01, 0.02, 0.075, 0.1, 2.5, 10, and 100 μg PZQ or TRANS enantiomers/ml, respectively, before being transferred to drug-free medium for another 20 h. PZQ is used as a racementa in the therapy, and its effect is attributed to the R(−)-enantiomer. R(−)-PZQ and R(−)-TRANS proved to be at least 105 times more effective than the respective S(+)enantiomers, causing tegumental damage and surface blebbing onS. mansoni. As judged from the effective doses in 50% of the worms (ED50 values); R(−)-PZQ and R(−)-TRANS showed nearly the same efficacy against adultS. mansoni. Male worms reacted more sensitively than did females. As determined by scanning electron microscopy, alterations in lethally damaged worms depended on the drug used, even following incubation at the lowest concentration tested (0.01 μg/ml). Worms exposed to R(−)-TRANS were elongated, whereas treatment with R(−)-PZQ led to contractions and twisted parasites. Both compounds caused excessive surface blebbing along the dorsal side of the worms' tegument.
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  • 10
    ISSN: 1022-1352
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: (4S,5S)-4-methyl-5-phenyl-2-(4-vinylphenyl)-2-oxazoline(1) was prepared. The anionic polymerisation of 1 was initiated in toluene with butyllithium (BuLi) at -78°C to afford poly(1) of narrow molecular weight distribution. The resulting poly(1) was immobilised on modified silica gel to give chiral stationary phases for the separation of racemic compounds.
    Additional Material: 1 Ill.
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