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Enantiomers of thalidomide: blood distribution and the influence of serum albumin on chiral inversion and hydrolysis
Author(s) -
Eriksson Tommy,
Björkman Sven,
Roth Bodil,
Fyge Åsa,
Höglun Peter
Publication year - 1998
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/(sici)1520-636x(1998)10:3<223::aid-chir4>3.0.co;2-a
Subject(s) - chemistry , enantiomer , human serum albumin , in vivo , hydrolysis , pharmacokinetics , blood proteins , albumin , serum albumin , blood plasma , chromatography , stereochemistry , biochemistry , pharmacology , biology , medicine , microbiology and biotechnology
The aim of this investigation was to elucidate the distribution and reactions of the enantiomers of thalidomide at their main site of biotransformation in vivo, i.e., in human blood. Plasma protein binding, erythrocyte: plasma distribution, and the kinetics of chiral inversion and degradation in buffer, plasma, and solutions of human serum albumin (HSA) were studied by means of a stereospecific HPLC assay. The enantiomers of thalidomide were not extensively bound to blood or plasma components. The geometric mean plasma protein binding was 55% and 66%, respectively, for (+)‐(R)‐ and (−)‐(S)‐thalidomide. The corresponding geometric mean blood:plasma concentration ratios were 0.86 and 0.95 (at a haematocrit of 0.37) and erythrocyte:plasma distributions were 0.58 and 0.87. The rates of inversion and hydrolysis of the enantiomers increased with pH over the range 7.0–7.5. HSA, and to a lesser extent human plasma, catalysed the chiral inversion, but not the degradation, of (+)‐(R)‐ and (−)‐(S)‐thalidomide. The addition of capric acid or preincubation of HSA with acetylsalicylic acid or physostigmine impaired the catalysis to varying extents. Correction for distribution in blood enhances previously observed differences between the pharmacokinetics of the enantiomers in vivo. The findings also support the notion that chiral inversion in vivo takes place mainly in the circulation and in albumin‐rich extravascular spaces while hydrolysis occurs more uniformly in the body. In addition, the chiral inversion and hydrolysis of thalidomide apparently occur by several different mechanisms. Chirality 10:223 – 228, 1998 . © 1998 Wiley‐Liss, Inc.