Chirality in Biology
601
in October 2002 elicited 703 ‘‘hits.’’ The
topic is extremely complex and only a
brief account is possible here. A com-
plication is that pharmacologists consider
two main areas – pharmacodynamics and
pharmacokinetics. The Frst concerns ac-
tual physiological effects caused by a drug
and the nature of the binding to recep-
tor sites as well as correlation of chemical
structure with physiological activity. Phar-
macokinetics concerns differences in the
rate of transport of the drug to the receptor
sites, in clearance rates, and the possi-
bility of transformation to other products
that themselves might or might not have a
physiological action.
Medicinal drugs are of three general
types: some such as aspirin are achiral
and of no concern here; chiral drugs ob-
tained by chemical synthesis are usually
racemic mixtures (e.g. fluoxetine, trade
name Prozac); chiral drugs obtained from
natural sources such as plants or from
fermentations are usually single enan-
tiomers (e.g. morphine, penicillin). There
has been considerable interest among
pharmaceutical companies in developing
single-enantiomer forms or in switch-
ing from a racemic mixture already in
use to a single enantiomer – the so-called
racemic switch
(a racemic switch may also
provide a new drug when patents are
expiring). The stakes are high. In 2001,
worldwide sales of formulated pharmaceu-
tical products totaled $410 billion; single-
enantiomer drugs accounted for sales of
$147 billion (36%).
In 1992, the US ±ood and Drug Adminis-
tration, ±DA, issued a policy statement for
the development of stereoisomeric drugs
that was mainly concerned with chiral
drugs and the need for appropriate testing
of enantiomers. However, under certain
circumstances, the development and use
of racemic mixtures was to be allowed. This
±DA statement recognized three pharma-
codynamic cases:
Case 1. Both drug enantiomers have
similar, desirable pharmacological effects.
This is the case with ibuprofen, a non-
steroidal antiinflammatory agent, sold as
a racemate over the counter under various
brand names (e.g. Advil, Motrin, Nuprin).
It contains a single chiral center. Both
enantiomers are antiinflammatory, but
(
S
)-(
+
)-ibuprofen (±ig. 14a) is the more ac-
tive and lacks some side effects. A racemic
switch has led to the availability of (
S
)-
ibuprofen in Austria and Switzerland, but
this form was not approved for the United
States. Ibuprofen also shows an inter-
esting pharmacokinetic property. During
metabolism, the (
R
)-(
) enantiomer un-
dergoes conFgurational inversion forming
the (
S
)-(
+
)-ibuprofen. Thus, administra-
tion of racemic ibuprofen to humans leads
to excreted material in which the enan-
tiomer composition is 70% (
S
) and 30%
(
R
).
Another Case 1 situation is warfarin.
When used as an anticoagulant in humans,
the enantiomers are equipotent. However,
warfarin
is
also
used
as
a
selective
rodenticide, and in this application (
S
)-(
)-
warfarin (±ig. 14b) is about 6 to 7 times
more potent than the (
R
)f
o
rm
.T
h
e
r
e
may be a pharmacokinetic effect – the
(
S
) form has an approximately twofold
longer
half-life
(15
.
4
±
2
.
8 h) than
the
(
R
) enantiomer.
±or the serotonin (5-hydroxytryptamine)
uptake inhibitor fluoxetine (trade name,
Prozac), both enantiomers also have an
almost equipotent blocking action. In this
case, there was an economic reason for
pursuing a racemic switch – the patent
on
the
racemate
began
to
expire
in
2001. With the single-enantiomer (
R
)form
(±ig. 14c), there was a small but signiFcant
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