Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide
作者:
Tommy Eriksson,
Sven Bjöurkman,
Bodil Roth,
Årsa Fyge,
Peter Höuglund,
期刊:
Chirality
(WILEY Available online 1995)
卷期:
Volume 7,
issue 1
页码: 44-52
ISSN:0899-0042
年代: 1995
DOI:10.1002/chir.530070109
出版商: Alan R. Liss, Inc.
关键词: thalidomide enantiomers;stereospecific analysis;high‐performance liquid chromatography;in vitro kinetics;chiral inversion;stereoselective pharmacokinetics
数据来源: WILEY
摘要:
AbstractThe 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 ab
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