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.