Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide.

Content Provider	Semantic Scholar
Author	Eriksson, Tommy Bjoerkman, Sven Dr Roth, Bodil Fyge, A. Höglund, Peter
Copyright Year	1995
Abstract	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.
Starting Page	44
Ending Page	52
Page Count	9
File Format	PDF HTM / HTML
DOI	10.1002/chir.530070109
PubMed reference number	7702998
Journal	Medline
Volume Number	7
Issue Number	1
Alternate Webpage(s)	http://www.k-faktor.com/contergan/files/racemization.pdf
Alternate Webpage(s)	https://doi.org/10.1002/chir.530070109
Journal	Chirality
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article