Stereospecific Determination, Chiral Inversion In Vitro and Pharmacokinetics in Humans of the Enantiomers of Thalidomide

Tommy Eriksson, Sven Bjorkman, Bodil Roth, Asa Fyge, and Peter Hoglund


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 phannacokinetics 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 chal 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 6.17 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.

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Hospital Pharmacy, Malmö General Hospital, Malmö, Sweden (T.E., S.B., B.R., A.F.); and Department of Clinical Phamology, University of Lund, Lund, Sweden (P.H.).

Chirality 1995; 7(1):44-52
Copyright © 1995 by Wiley-Liss, Inc.

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