Pharmacological Importance of Chiral Separations - Chiral Separations by Capillary Electrophoresis - page 6

responsible for toxic effects. Thus, the racemate can contain up to 50% of impu-
rity or ballast. Examples are escitalopram and levodopa. Escitalopram is the active
S -enantiomer of citalopram, a selective serotonin reuptake inhibitor. It is approxi-
mately 100 times more potent as reuptake inhibitor than its R -enantiomer [14-17].
While the R -enantiomer is practically devoid of uptake inhibition potency, it does
appear to interact with histamine receptors. Therefore, the single enantiomer drug
escitalopram will be less sedating than the racemate [16]. In addition, it has been
shown that R -citalopram counteracts the binding of escitalopram to the allosteric
site of the serotonin transporter [18]. Serious side effects limited the use of racemic
dopa for the treatment of Parkinson's disease. These adverse effects included nau-
sea, vomiting, anorexia, involuntary movements, and granulocytopenia. The use of
levodopa instead of the racemate was found to halve the required dose, to reduce
toxicity, and to improve the motor function. The occurrence of granulocytopenia was
related to the dextrorotary enantiomer [3].
Secondly, the two enantiomers can have almost identical qualitative and quan-
titative pharmacological activity. The enantiomers of promethazine, for example,
have nearly identical antihistaminic properties and toxicity [5,19,20]. Similarly, both
enantiomers of l ecainide and propafenone have equivalent antiarrhythmic potency
[5,20,21].
Thirdly, the enantiomers can possess similar pharmacological properties;
however, they can differ in potency. Most chiral drugs belong to this category.
Examples of this class of chiral drugs are warfarin, verapamil, levocetirizine,
and ( R , R )-methylphenidate. S -warfarin has a i ve times larger anticoagulant
potency than its antipode R -warfarin [15,22,23]. S -verapamil is approximately
20 times more potent than its R -enantiomer with regard to negative dromotropic
effects on atrioventricular node conduction [24]. Levocetirizine has an approxi-
mately 30-fold higher afi nity for human H 1 -receptor than dextrocetirizine [25].
( R , R )-methylphenidate, used for the treatment of attention-dei cit hyperactivity
disorder, is approximately 10 times more potent than ( S , S )-methylphenidate in
the inhibition of dopamine and noradrenaline from striatal and hypothalamic
synaptosomes respectively [26].
Fourthly, enantiomers can have qualitatively different pharmacological activities.
For example, dextropropoxyphene is used as an analgesic while levopropoxyphene
has antitussive properties. Another example is the mixed adrenoreceptor blocker
labetalol. The ( S , R )-isomer has α -blocking effects, while the β -blocking activities

are due to the ( R , R )-isomer [19,27].
According to these pharmacodynamic differences seen between enantiomers,
in several cases the use of a single enantiomer instead of the racemate could be
suggested. However, it is not always clear-cut as seen in the example of ibuprofen.
Although R -ibuprofen is not active, it is the precursor of the active S -enantiomer
via a unidirectional metabolic chiral inversion pathway (Figure 1.4). R -ibuprofen
is metabolized to an intermediary R -CoA thioester which is then epimerized to an
S -CoA thioester and in turn converted to S -ibuprofen. This results in a nonsignii cant
difference in activity in vivo between the racemate and the individual enantiomers
[3,20,28-31]. Another example is the well-known thalidomide. Racemic thalidomide
was introduced as a relatively safe sedative drug in the late 1950s, but soon thereafter