Thalidomide, chirality

Tommy Eriksson, Sven Bjorkman, Bodil Roth, Asa Fyge, Peter Hoglund Stereospecific Determination, Chiral Inversion in vitro and Pharmacokinetics in Humans of the Enantiomers of Thalidomide, Chirality 7,44-52 (1995)... 

Fyge, A., Hoglund, P. Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality, 1995, 7, 44-52. 

T. Eriksson, S. Bjorkman, B. Roth, A. Fyge, P. Hoglund, Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide, Chirality 7 (1995) 44-52. T. Eriksson, S. Bjorkman, B. Roth, A. Fyge, P. Hoglund, Enantiomers of thalidomide Blood distribution and the influence of serum albumin on chiral inversion and hydrolysis. Chirality 10 (1998) 223-228. 

A much more serious drawback to using chiral drugs as racemic mixtures is illustrated by thalidomide briefly employed as a sedative and antinausea drug in Europe during the period 1959-1962 The desired properties are those of (/ ) thalidomide (S) Thalido mide however has a very different spectrum of bio logical activity and was shown to be responsible for over 2000 cases of serious birth defects in children born to women who took it while pregnant... 

The ideal solubility equation has significant value in chiral systems, where a single enantiomer is desired as the product [20]. The behaviour of chiral compounds is very important in biological systems and in drug development, where it is typical for just one enantiomer of an API to be biologically active. The undesired enantiomer may be inert, or possess more serious toxicity effects, as in the case of Thalidomide. Many enantiomeric systems form three discrete solid phases, depending on the solution concentration. Pure crystals of each enantiomer will form at high concentrations of their respective enantiomer. At... 

A four-compartment model consisting of a two-compartment model for each enantiomer, with elimination from both compartments, connected by rate constants for chiral inversion was fitted to the concentration data, whereas the sedative effects were correlated with the blood concentrations of R- and S-thalidomide by means of logistic regression. PK modeling predicted that varying the infusion time of a fixed dose of S-thalidomide between 10 min and 6 h would have little influence on the maximal blood concentration of formed R-thaKdomide. These effects may chiefly be exerted by S-thalidomide, but the enantiomers are interconverted in vim... 

Enantiomers are characterized as nonsuperimposable mirror images. Enantiomers are said to be chiral (note that some diastereomers may be chiral as well). In the context of the same bonding pattern or connectivity, which atoms are bonded to which, enantiomers have handedness and are related to each other as the right hand is related to the left hand. In the specific example we saw earlier, the carbon atom is linked to four different atoms. Such molecules have non-superimposable mirror images. Stereoisomerism occurs in some molecules that do not have such a carbon atom but these cases are more exotic than we need to worry about here. Stereoisomers frequently have different, and sometimes strikingly different, biological properties, exemplified by the thalidomide case. 

The importance of chiral factors in disposition and toxicity has been fully recognized only relatively recently, although important examples have been known for some time. For instance the S(—) enantiomer of thalidomide is known to have greater embryotoxicity than the R(+) enantiomer (see chap. 7). Another example in which a particular isomer of a metabolite is responsible for a carcinogenic effect is the exo-oxide of aflatoxin Bi, discussed later in this chapter (Fig 5.14). 

The use of antibiotic-based CSPs has been reported in capillary electrochromatography (CEC) for chiral resolution [60]. Teicoplanin CSP covalently bonded to silica gel was used to resolve the enantiomers of tryptophan and dinitrobenzoyl leucine by CEC [61]. Good levels of enantioselectivity were obtained with optimized separations. Vancomycin covalently bonded to silica gel was also evaluated in CEC for the chiral resolution of thalidomide and jS-adrenergic blocking agents under all the three mobile phase modes. The... 

FIGURE 1 Chromatograms of the chiral resolution of thalidomide on the Prodigy C18 column using phosphate buffer (10 mM, pH 4.0)-ethanol (95 5, v/v) as the mobile phase containing /i-cydodextrin (20 mM) as the CMPA. (From Ref. 10.)... 

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