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Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide
Author(s) -
Eriksson Tommy,
Bjöurkman Sven,
Roth Bodil,
Fyge Årsa,
Höuglund Peter
Publication year - 1995
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530070109
Subject(s) - enantiomer , chemistry , pharmacokinetics , thalidomide , in vivo , elimination rate constant , stereochemistry , stereospecificity , high performance liquid chromatography , reaction rate constant , chromatography , pharmacology , kinetics , organic chemistry , volume of distribution , medicine , physics , microbiology and biotechnology , quantum mechanics , multiple myeloma , biology , catalysis , immunology
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.