STEREOSPECIFIC DETERMINATION, CHIRAL INVERSION IN-VITRO AND PHARMACOKINETICS IN HUMANS OF THE ENANTIOMERS OF THALIDOMIDE
STEREOSPECIFIC DETERMINATION, CHIRAL INVERSION IN-VITRO AND PHARMACOKINETICS IN HUMANS OF THE ENANTIOMERS OF THALIDOMIDE
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DOI：
10.1002/chir.530070109
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发表时间：
1995-01-01
期刊：
影响因子：
2
通讯作者：
HOGLUND, P
中科院分区：
文献类型：
--
作者：
ERIKSSON, T;BJORKMAN, S;HOGLUND, P
本工作的目的是(1)建立沙利度胺对映体在血液中的高效液相色谱法，(2)研究它们在人血中的转化和降解，(3)研究健康男性志愿者口服(+)-(R)-和(-)-(S)-沙利度胺对映体或外消旋体的药代动力学。用三苯甲酰基纤维素柱直接拆分沙利度胺对映体。37℃时(+)-(R)-沙利度胺和(-)-(S)-沙利度胺在血液中的手性转化平均速率常数分别为0.30和0.31h(-1)。降解速率常数分别为0.17和0.18h(-1)。在人体内有快速的相互转化，平衡时(+)-(R)-对映体占主导地位。(+)-(R)-和(-)-(S)-沙利度胺的药代动力学可用两个速率常数相连的一室模型进行手性转化。体内转化的平均速率常数分别为0.17h(-1)(R对S)和0.12h(-1)(S对R)，消除速率常数分别为0.079 h(-1)(R)和0.24 h(-1)(S)，即较快的消除(-)-(S)对映体的速率。(+)-(R)-和(-)-(S)-沙利度胺在治疗或不良反应方面的假定差异将在很大程度上通过体内快速相互转换而消除。(C)1995年Wiley-Liss公司
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 degrees 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. (C) 1995 Wiley-Liss, Inc.