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

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.