Page 347 - Chiral Separation Techniques

340 13 International Regulation of Chiral Drugs

active S(+)-isomer; thus the reduction in dose of the single enantiomer required to
achieve the same clinical effect is not half that of the racemate [13]. Interconversion
is also the reason why it is unlikely that development of the single R(+)-enantiomer
of thalidomide would prevent the well-known teratogenic side-effects of this drug
which are probably associated with the S(–)-enantiomer. The R-isomer is converted
following administration to the S-isomer in man, but not in some other species. This
example illustrates the need for studies on a case-by-case basis to establish the pat-
terns of activity and pharmacokinetics for each pair of enantiomers and for careful
assessment of the future development of either the racemate or pure enantiomer.

13.7 Concluding Remarks

Regulation of chiral drugs is now well established, and has had the effect of pro-
ducing a higher ratio of single enantiomer to racemic compounds for new synthetic
drugs on the market. New analytical and preparative techniques will make it easier
in the future to develop single enantiomers. There is no real evidence that the num-
ber of achiral drugs is increasing to avoid the problems associated with enantiopu-
rity. Therefore it seems safe to assume that the technical methods for controlling chi-
ral drugs have developed to a stage where many of the challenges presented to the
analyst can be solved.
There will be a continued need for enantiospecific methods of preparation and
analysis, not only to ensure the quality of the final drug substance and reference
materials, but also to control starting materials used for their manufacture, and key
intermediates during synthesis. Likewise, specific and sensitive bioanalytical meth-
ods will be required to follow the fate of individual enantiomers after their adminis-
tration.

References

[1] A. R. Cushny, Biological relations of optically isomeric substances, Balliere, Tindall and Cox, Lon-
don, 1926.
[2] P. Jenner, B. Testa, Influence of stereochemical factors on drug disposition, Drug Metab. Rev. 1973,
2, 117–184.
[3] E. J. Ariëns, Stereochemistry, a basis for sophisticated non-sense in pharmacokinetics and clinical
pharmacology, Eur. J. Clin. Pharmacol. 1984, 26, 663–668.
[4] E. J. Ariëns, Stereochemistry: a source of problems in medicinal chemistry, Med. Res. Rev. 1986,
6, 451–466.
[5] A. R. Fassihi, Racemates and enantiomers in drug development, Int. J. Pharmaceutics 1993, 92,
1–14.
[6] R. R. Shah, Clinical pharmacokinetics: current requirements and future perspectives from a regula-
tory point of view, Xenobiotica, 1993, 23, 1159–1193.