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  • 1
    ISSN: 0899-0042
    Keywords: thalidomide enantiomers ; in vitro kinetics ; blood distribution ; human serum albumin ; chiral inversion ; plasma protein binding ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The aim of this investigation was to elucidate the distribution and reactions of the enantiomers of thalidomide at their main site of biotransformation in vivo, i.e., in human blood. Plasma protein binding, erythrocyte: plasma distribution, and the kinetics of chiral inversion and degradation in buffer, plasma, and solutions of human serum albumin (HSA) were studied by means of a stereospecific HPLC assay. The enantiomers of thalidomide were not extensively bound to blood or plasma components. The geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. The corresponding geometric mean blood:plasma concentration ratios were 0.86 and 0.95 (at a haematocrit of 0.37) and erythrocyte:plasma distributions were 0.58 and 0.87. The rates of inversion and hydrolysis of the enantiomers increased with pH over the range 7.0-7.5. HSA, and to a lesser extent human plasma, catalysed the chiral inversion, but not the degradation, of (+)-(R)- and (-)-(S)-thalidomide. The addition of capric acid or preincubation of HSA with acetylsalicylic acid or physostigmine impaired the catalysis to varying extents. Correction for distribution in blood enhances previously observed differences between the pharmacokinetics of the enantiomers in vivo. The findings also support the notion that chiral inversion in vivo takes place mainly in the circulation and in albumin-rich extravascular spaces while hydrolysis occurs more uniformly in the body. In addition, the chiral inversion and hydrolysis of thalidomide apparently occur by several different mechanisms. Chirality 10:223-228, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-8744
    Keywords: ketamine ; midazolam ; mass balance ; brain ; cerebral blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF)by one third, as measured by intermittent 133Xewashout. By means of pharmacodynamic models, the effects on the CBFcould be predicted from the arterial drug concentrations. The high-resolution CBFvs. time curves thus generated allowed the calculation of cerebral drug levels from arteriovenous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF,ketamine and midazolam decreasetheir own rateof transport to the brain, the immediate 30-35% drops in CBFgiving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBFis determined mainly by the effects of the anesthetics and by the arterial CO 2 tension. CBFchanges in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects.
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  • 3
    ISSN: 0899-0042
    Keywords: thalidomide enantiomers ; stereospecific analysis ; high-performance liquid chromatography ; in vitro kinetics ; chiral inversion ; stereoselective pharmacokinetics ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The purposes of this work were (1) to develop a high performance liquid chromatographic (HPLC) assay for the enantiomers of thalidomide in blood, (2) to study their inversion and degradation in human blood, and (3) to study the pharmacokinetics of (+)-(R)- and (-)-(S)-thalidomide after oral administration of the separate enantiomers or of the racemate to healthy male volunteers. The enantiomers of thalidomide were determined by direct resolution on a tribenzoyl cellulose column. Mean rate constants of chiral inversion of (+)-(R)-thalidomide and (-)-(S)-thalidomide in blood at 37°C were 0.30 and 0.31 h-1, respectively. Rate constants of degradation were 0.17 and 0.18 h-1. There was rapid interconversion in vivo in humans, the (+)-(R)-enantiomer predominating at equilibrium. The pharmacokinetics of (+)-(R)- and (-)-(S)-thalidomide could be characterized by means of two one-compartment models connected by rate constants for chiral inversion. Mean rate constants for in vivo inversion were 0.17 h-1 (R to S) and 0.12 h-1 (S to R) and for elimination 0.079 h-1 (R) and 0.24 h-1 (S), i.e., a considerably faster rate of elimination of the (-)-(S)-enantiomer. Putative differences in therapeutic or adverse effects between (+)-(R)- and (-)-(S)-thalidomide would to a large extent be abolished by rapid interconversion in vivo. © 1995 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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