Download Chirality and its Importance in Pharmaceutical Field- An

Somagoni Jagan Mohan et al. : Chirality and Its Importance in Pharmaceutical Field
Review
- An Article
Overview
309
Chirality and its Importance in Pharmaceutical Field- An Overview
Somagoni Jagan Mohan1, Eaga Chandra Mohan1, and Madhsudan Rao Yamsani1*
1
Centre for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical Sciences,
Kakatiya University, Warangal - 506 009 (A.P.) India
ABSTRACT: Until recently, the majority of single-isomer drugs available were those derived from natural
sources (e.g. morphine, epinephrine, hyoscine), and racemates predominated. There is now clear evidence of
a trend in the pharmaceutical industry towards the development of chiral drugs. Several factors have
influenced this trend, which has occurred independently and in parallel with a quest in the industry totally to
develop more potent, selective and specific drugs. The process is equivalent to developing a new active
substance and requires a new application, but data on the racemate may be used as appropriate, together
with ‘bridging studies’. There is, however, limited potential in the market for the degree of therapeutic benefit
obtained to justify the degree of investment. The real benefit of chiral technology lies in its application in the
search for novel chemical entities and its appropriate formulation. This paper gives a brief idea about the
importance of chirality, nomenclature, use of chiral excipients in formulations containing chiral drugs,
stereoselective dissolution, stereoselective kinetics and dynamics, separation and estimation techniques and
some interactions of chiral drugs. This paper also gives a brief overview of work done on chirality from
formulation point of view.
KEY WORDS: Chirality, chiral excipients, chiral drugs, chiral formulation, chiral interactions.
Introduction
Over one third of marketed drugs world wide are chiral,
and regulators will now only approve new chiral drugs in
the single enantiomer form, and even then insist on full
profiling of the role of the individual enantiomers in vivo
(Collins et al., 1992).
Polarized light is rotated when passing through
solutions containing chiral molecules (but not when
passing the racemic mixtures). Optical isomers rotate the
light in an equal degree but in opposite direction. If the
enantiomer rotates the light to the right, it will be indicated
as dextrorotatory (Latin:dextro), “d” or “(+)”. Optical
isomers that rotate light to the left, on the other hand will
be indicated as levorotatory (Latin:Laevus), “l” or “(-)”.
According to the Fischer convetion the absolute
configuration around a chiral center can be noted as D or L
(Millership et al., 1993). This notation, which is mainly
used for amino acids and carbohydrates, correlates the
configuration of a chiral center to the configuration of D or
L glyceraldehydes. The R/S notation (from Latin; rectus
(right) and sinister (left), which has largely replaced the
D/L notation, is related to the Cahn-Ingold-Prelog
*Corresponding author: Prof. Y. Madhusudan Rao,
Centre for Biopharmaceutics and Pharmacokinetics,
University College of Pharmaceutical Sciences,
Kakatiya University, Warangal - 506 009 (A.P.), India.
Tel.: +91-870-2438844
Fax: +91-870-2570543
E-mail: [email protected]
309
convetion, and can also be used for molecules containing
more than one chiral center (Islam et al., 1997).
Significance of Chirality
Most of the molecules of importance to living systems are
chiral, e.g. amino acids, sugars, proteins and nucleic acids.
An interesting feature of these biomolecules is that in
nature they usually exist in only one of the two possible
enantomeric forms (Crossley R, 1995). When a chemist
synthesizes a chiral molecule in an achiral environment
using achiral starting materials, an equal mixture of the
two possible enantiomers (i.e. a racemic mixture) is
produced. In order to make just one enantiomer, some
enantioriched material, reagent, catalyst, or template must
be presenting the reaction medium. Oftentimes, only a
single enantiomer of a chiral molecule is desired, as in the
case when the target molecule is a chiral drug that will be
used in living systems. Drug molecules can be linked to
any keys that fit into locks in the body and elicit a
particular biological response. Since the ‘locks’ in the
living organisms are chiral, and exist only in one of the
two possible enantiomeric forms, only one enantiomer of
the ‘key’ molecule should be used. In general, the use of
both enantiomers in a racemic formulation of a chiral drug
may be wasteful, and sometimes even introduces
extraneous material that may lead to undesired side effects
or adverse reactions (Stinson, 1998). This hypothetical
interaction between two enantiomers of a chiral drug can
be understood better from the Fig 1.
310
International Journal of Pharmaceutical Sciences and Nanotechnology
Active Enantiomer
Volume 1 • Issue 4 • January-March 2009
Formulation:
Inactive Enantiomer
Mirror plane
Fig. 1 Hypothetical interaction between the two
enantiomers of a chiral drug and its binding site.
The active enantiomer has a three dimentional structure
that allows the drug domain A to interact with binding site
domain a, B to interact with b, C to interact with c. In
contrast, the inactive enantiomer cannot be aligned to bind
the same three sites simultaneously. The difference in three
dimentional structure allows the active enantiomer to bind
and have a biological effect, where as the inactive
enantiomer can not. Different drugs showing different
activities with different enantiomers are given in Table 1.
Table 1. Examples of drugs showing different activities
with different enantiomers (Indra , 2004).
Chirality influences drug delivery because a single
enantiomer or a non- racemic blend may have improved
solubility, dissolution, and stability. In addition, many
available pharmaceutical excipients (e.g., cellulose and its
derivatives) either naturally occur as single enantiomers or
are derivatives of the latter chiral molecules. These
stereochemically pure molecules may interact with other
chiral molecules (i.e., the active ingredient) and form
stereoisomers. The latter will have physicochemical
properties different from the original chiral molecule. For
example, the presence of heptakis (2,6-di-O-ethy l)-betacyclodextrin results in stereoselective dissolution of
tiaprofenic acid. While this stereoselective release did not
result in stereoselective bioavailability, it highlights the
potential implication of the effect of chirality on
physicochemical properties of drugs. Similar to the solid
dosage forms containing chiral excipients, biological
membranes may provide chiral environments. Most drugs
cross the gastrointestinal membrane through simple
passive diffusion; thus, no stereoselectivity in the process
is expected (Eichelbaum, 1996).
Chiral excipients: With the advent of stereospecific
analytical methods in recent years, more attention has been
drawn to the influence of chiral excipients on the
modification of in vitro release and in vivo disposition of
chiral drugs. Chiral excipients have been widely used in
pharmaceutical dosage forms. Different chiral excipients and
their pharmaceutical applications are given in the Table 2.
Few drugs that show the importance of chiral switch:
Cinchona Alkaloids
While (-)-Quinine and (+)-Quinidine are diastereomers,
they are not enantiomers, as is also the case with (-)cinchonidine and (+)-cinchonine. Of these four alkaloids,
(-)-Quinine, (-)-cinchonidine and (+)-cinchonine are all
antimalarials. While (+) Quinidine also possesses antimalarial properties, but it is normally prescribed as
antiarrhythmic to regulate heartbeat (Balkovec et al.,
2001).
Table 2. Selected chiral excipients and their pharmaceutical applications (Indra, 2004).
Excipient
Celluloses
Carboxymethylcellulose calcium
Ethylcellulose
Hydroxyethyl cellulose
Hydroxypropyl cellulose
Hydroxypropylmethyl cellulose Phthalate
Microcrystalline cellulose
Cellulose acetate
Cellulose acetate butyrate
Cellulose acetate phthalate
Major Applications
Suspending agent, stabilizer, coating agent
Binder, coating material, viscosity builder
Viscosity builder, binder, film former, dissolution modifier
Viscosity builder, binder, stabilizer
Enteric coating agent, taste masking
Binder, diluent, stabilizer, disintegrant,
Dissolution modifier, film coating agent
Dissolution modifier, film former
Dissolution modifier, film former
Table 2. Contd…
Somagoni Jagan Mohan et al. : Chirality and Its Importance in Pharmaceutical Field - An Overview
B. Starch, Sugars and Derivatives
Alginic acid
Carrageenan
Dextrose
Fructose
Guar gum or Galactomannan
Lactose
Mannitol
Maltose
Pectin
Scleroglucan
Sorbitol
Starch
Sucrose
Xanthan gum
C. Cyclodextrins
Beta-cyclodextrin
Hydroxypropyl β- cyclodextrin Heptakis
(2,6-di-O-ethyl)- β- cyclodextrin
D. Acids
Ascorbic acid
Lactic acid
Malic acid
Tartaric acid
E. Amino Acids, Peptides, and Derivatives
Arginine
Aspartame
Bovine serum albumin
Human serum albumin
Lysine
Protamine
F. Fats, Oils, Essential oils
Medium chain triglycerides
Carvacrol
Carvone
1,8, cineole
± linalool
D-limonene
Menthone
L-menthol
α-tocopherol
Binder, disintegrant, viscosity builder
Sustained release matrix, suspending agent
Diluent, sweetener
Diluent, sweetener, dissolution enhancer
Binder, disintegrant, viscosity builder,
Diluent, sweetener
Diluent, sweetener, bulking agent for lyophilized product
Diluent, sweetener
Dissolution modifier, dispersant
Dissolution modifier
Diluent, sweetener, humectant
Diluent, binder
Sweetener
Viscosity builder, suspension stabilizer
Complexing agent, dissolution enhancer, Stabilizer
Complexing agent, dissolution enhancer, Stabilizer
Anti-oxidant
Acidifying agent. Acidulant,
Acidulant, buffering agent, antioxidant, flavouring agent
Effervescent agent, diluent
Stabilizer
Sweetener
Solubility enhancer ( for biomolecules)
Solubility enhancer ( for biomolecules)
Stabilizer
Stabilizer
Emulsifying agent, suspending agent in emulsion
systems, absorption enhancer, dissolution modifier
Flavor, Permeation enhancer
Flavor, Permeation enhancer
Flavor, Permeation enhancer
Flavor, Permeation enhancer
Flavor, Permeation enhancer
Flavor, Permeation enhancer
Flavor, Permeation enhancer
Antioxidant
Ascorbic acid:
As (+)-Ascorbic acid and (-)-Erythorbic acid (Fig. 1a) are
often labeled as L-ascorbic acid and D-erythorbic acid,
respectively, there is often a misconception that these two
items are enantiomers. These are not enantiomers, but are
diastereomers as the structures are not mirror images. (-)Erythorbic acid exhibits only 5% of the anti-ascorbutic
activity compared to (+)-Ascorbic acid (Friedman et al.,
1999).
Fig. 1a Ascorbic acid.
311
312
International Journal of Pharmaceutical Sciences and Nanotechnology
Thalidomide:
The use of thalidomide (Fig. 2) led to a tragedy in the
1960s in Europe. The drug was prescribed to pregnant
women to counter morning sickness. Studies later
suggested that these effects were caused by the Senantiomer and that the R-enantiomer contained the
desired therapeutic activity. More recently, studies have
concluded that both enantiomers of thalidomide are
unstable and spontaneously epimerize to form the racemate
in-vivo in humans. The in-vitro studies demonstrated the
hydrolysis products 5-hydroxy-thalidomide and 5’hydroxy-thalidomide while in-vivo only the 5'-hydroxy
metabolite was found, in low concentrations, in plasma
samples from eight healthy male volunteers who had
received thalidomide orally (Meyring et al., 2002).
Volume 1 • Issue 4 • January-March 2009
pharmacokinetic differences between the enantiomers with
(S)- albuterol being cleared more slowly. The (S)enantiomer tends to accumulate in preference to the
therapeutically
effective
(R)-enantiomer.
These
pharmacokinetic and pharmacodynamic differences
provided the basis for the chiral switch patent of albuterol
to levalbuterol, (R)-albuterol, which has the same
bronchodilator activity as racemic albuterol, but has a
superior side-effect profile (Nowak, 2003).
Fig. 3 Albuterol.
(S)-Ibruprofen and (S)-Ketoprofen:
R-Thalidomide
Sedative-hypnotic
S-Thalidomide
Mutagenic
Fig. 2 Thalidomide.
The chiral center of the thalidomide enatiomers is
unaffected by the stereoselective biotransformation
process. (3'R,5'R)-trans-5'-hydroxythalidomide is the main
metabolite of (R)-thalidomide, which epimerizes
spontaneously to give the more stable (3'S,5'R)-cis isomer.
On the contrary, (S)-thalidomide is preferentially
metabolized by hydroxylation in the phthalimide moiety,
resulting in the formation of (S)-5-hydroxythalidomide.
Although Thalidomide is tainted from its past history, it
(and analogs) have recently been a subject of numerous
studies. In 1998 the U.S. Food and Drug Administration
approved thalidomide for use in treating leprosy symptoms
and studies indicate some promising results for use in
treating symptoms associated with AIDS, behchet disease,
lupus,
sjogren
syndrome,
rheumatoid
arthritis,
inflammatory bowel disease, macular degeneration, and
some cancers (Eriksson et al., 2001).
Both (S)-Ibruprofen and (S)-Ketoprofen (Fig. 4 & 5) are
the chiral switch drugs of the popular racemates. The
activities of the two enantiomers of Ibuprofen and
ketoprofen are essentially indistinguishable in vivo, owing
to a unidirectional metabolic bioconversion of the (R)enantiomers to the (S)-enantiomers. The combination of
the stereospecificity of action, together with the
configurational inversion reaction provided drug
companies a rationale for the use of the (S)-enantiomers of
these drugs in therapy, as this reduces the total dose and
reduces the toxicity that is associated with the (R)enantiomer by removing the rate (and extent) of inversion
as a source of variation in metabolism and
pharmacological effects.
In
the
ketoprofen
case,
(S)-(+)-ketoprofen
(dexketoprofen) is several times more potent than the
racemate. The presentation of dexketoprofen as the
tromethamine salt provides three advantages: effective
analgesia at lower doses, rapid onset, and reduced gastric
irritation and improved tolerability (due to the novel salt
form) (Agranat et al., 2002).
Albuterol:
Albuterol is the racemate of 4-[2-(tert-butylamino)-1hydroxyethyl]-2 (hydroxymethyl) phenol (Fig. 3) and is
the leading bronchodilator, an adrenoceptor agonist that
can increase bronchial airway diameter without increasing
heart rate. The bronchodilator activity resides in (R)albuterol. (S)-albuterol, however, is not inert, as it
indirectly antagonizes the benefits of (R)-albuterol and
may have proinflammatory effects. There are
Fig. 4 (S)-Ibruprofen
Fig. 5 (S)-Ketoprofen.
Somagoni Jagan Mohan et al. : Chirality and Its Importance in Pharmaceutical Field - An Overview
Bupivacaine:
Racemic Bupivacaine (Fig. 6) currently is the most widely
used long-acting local anaesthetic. (S)-(-)-Bupivacaine
(Levobupivacaine), The S- enantiomer of bupivacaine, has
recently been introduced by Purdue Pharma LP under the
tradename Chirocaine® as a new long-acting local
anaesthetic with a potentially reduced toxicity compared
with bupivacaine (Gristwood et al, 1999). Numerous
studies have compared levobupivacaine with bupivacaine
and in most (but not all) studies there is evidence that
levobupivacaine is less toxic. Studies have also shown that,
following i.v. administration, levobupivacaine produces
significantly less effects on cardiovascular function than
racemic bupivacaine (Gristwood et al., 2002).
313
receptors. Metabolically, the formation of morphine
glucuronides is enantio- and regioselective in rats and
humans. In rat liver microsomes, natural (-)-morphine
formed only the 3-O-glucuronide, whereas the unnatural
(+)-morphine formed glucuronides at both the 3-OH and 6OH positions, with the 6-O-glucuronide being the principal
product. In human liver microsomes, both the 3-OH-and 6OH positions were glucuronidated with each of the
enantiomers, with the 3-O-glucuronide being the major
product with (-)-morphine, and the 6-OH position being
preferred with the (+)-enantiomer (Coughtrie et al., 1989).
Fig. 8 Morphine
Methadone:
Fig. 6 Bupivacaine.
Omeprazole:
Methadone (Fig. 9) has been used to assist heroin users in
withdrawal since the 1960’s. The opioid agonist properties
of racemic-methadone are ascribed almost entirely to only
one enantiomer, (R)-(-)-Methadone (Olsen et al., 1977).
Omeprazole (Fig. 7) is a gastric anti-secretory proton pump
inhibitor marketed under the tradenames Losec® and
Prilosec® by AstraZeneca and it developed the chiral
switch drug esomeprazole (which is the (S)-(-)-enantiomer
of omeprazole) based on the premise that therapeutic
benefit would be achieved by less inter-individual
variation, (slow versus rapid metabolizers), and that
average higher plasma levels would provide higher dose
efficiency in patients (Chong et al., 2003).
Fig. 9 Methadone.
Cocaine:
Fig. 7 Omeprazole.
Morphine:
The
opiate
receptors
are
stereospecific
and
pharmacological activity is dramatically dependent on
absolute configuration. For example, unnatural (+)morphine (Fig. 8) has extremely weak affinity for opiate
Similarly, the naturally occurring (1R,2R,3S,5S)-(-)cocaine (Fig. 10) is psychoactive whereas its enantiomer is
inactive. Metabolically, the behaviorally inactive (+)cocaine was found to hydrolyze at least 1,000 times faster
in baboon plasma than (–)-cocaine. Positron emission
tomography shows that (-)-cocaine is rapidly taken up in
the striata of both the human and baboon brain. No brain
uptake was seen for (+)-cocaine, although transport of
cocaine into the brain was not expected to be
stereoselective. The explanation for the lack of uptake was
determined to be very rapid metabolism of (+)-cocaine in
the blood 30 seconds after administration of labeled (+)cocaine, it was undetectable in plasma (Gatley et al., 1990).
314
International Journal of Pharmaceutical Sciences and Nanotechnology
Volume 1 • Issue 4 • January-March 2009
The quantitative determination of verapamil enantiomers
released by these systems was carried out
by
using
a
stereospecific
HPLC
method.
Hydroxypropylmethylcelluose,
beta-cyclodextrin,
Hydroxypropyl-beta-cyclodextrin, and cross linked
amylose did not show any stereoselective dissolution
properties while pectin, galactmannan and scleroglucan
seemed to give a slightly higher dissolution rate of the R,
compared with the S-enantiomer (Conte et al., 1996).
Selective separation and estimation of chiral drugs:
Fig. 10 Cocaine.
Amlodipine:
Amlodipine (Fig. 11) exhibits chirality, i.e., it exists as two
isomers. Moreover, the receptor binding studies have
shown that it the S (-) isomer of amlodipine that has L-type
calcium channel blocking activity. The R (-) isomer
exhibits a 1000-fold weaker calcium channel blocking
activity. Thus, the antihypertensive and antianginal activity
of amlodipine can be attributed only to S (-) amlodipine,
whereas the R (-) isomer can be regarded as inactive. Since
racemic amlodipine contains R (+) and S (+) isomer in 1:1
ratio, purifying the pharmacologically active S (-) isomer
can reduce the dose of racemic amlodipine to half (Lorfen
et al., 1994).
Fig. 11 Amlodipine.
1. Natural products
Isolation of natural products can be achieved in several
ways. Glutamic acid has been crystallized from gluten
hydrolysate. The very important carbohydrate sucrose
(table sugar) is collected from sugar cane and beets.
Glucose another key carbohydrate member of the chiral
pool is obtained from the hydrolysis of starch. Many
terpenes are extracted from the various plants in which
they are produced. Few monoterpenes and their plant
sources are given in Table 3.
Table 3. Monoterpenes and their plant sources (Liu, 1999).
Terpene
Source
α-Pinene
various pine trees
d-Limonene
orange, caraway,
l-Limonene
turpentine oils
dl-Limonene
turpentine oils
l- Carvone
spearmint oil
d-Carvone
caraway oil
dl-Carvone
ginger grass oils
l-Menthone
pinus palustrismell
Stereoselective Dissolution:
In most cases the modulation of the drug delivery rate from
modified-release formulations is achieved with polymers
also used as chiral stationary phases in liquid
chromatography. It is therefore hypothesized that the
interaction of the enantiomers with the excipient may lead
to differential delivery rates from the devices for each
enantiomers.
Preferential crystallization:
Stereoselective dissolution of verapamil hydrochloride
from the matrix tablets press coated with chiral excipients
evaluates the excipient stereoselective dissolution of (±)verapamil, a model racemic drug and, for this purpose,
different matrix compositions, a commercial product and a
particular device have been considered. The delivery
device, recently proposed for the delayed release of drugs,
consists of an active core containing the drug, coated by
compression with different types of polymeric materials.
Classical Resolution
Preferential crystallization of conglomerates is one of the
most attractive methods for separating optically inactive
isomers. However, only a few percent of racemic mixtures
exist as conglomerates, therefore this option has limited
availability.
Classical resolution remains the most widely used
technique for obtaining optically pure compounds for
synthesis of pharmaceuticals, agro chemicals and other
biologically active products a chiral acid or base resolving
is reacted with a racemic mixture and two diastereomeric
salts are formed. Different resolving agents used for the
classical resolution and drugs prepared with this technique
are given in Tables 4 & 5, respectively.
Somagoni Jagan Mohan et al. : Chirality and Its Importance in Pharmaceutical Field - An Overview
315
Table 4. Selected Common Resolving Agents (Sheldon, 1993)
Table 5. Drugs Prepared via Classical Resolution (Sheldon, 1999)
Kinetic Resolution
Kinetic resolution offers a means of obtaining optically
pure chemicals when preferential crystallization or
classical resolution methodologies are not available for the
desired compound. This technology relies on differing
activities of enantiomers when placed in a chiral environment.
Typically one enantiomer remains unreactive and the other
isomer forms a product with a chiral reagent. The two
compounds can be then separated with relative ease and
often with very high optical purities. Kinetic resolutions
can be achieved with chemical and biological catalysts.
Interactions
The two enantiomers of a racemic drug may interact with
each
other
at
different
pharmacokinetic
or
pharmacodynamic levels.
In addition to enantiomer-enantiomer interactions, a
racemic drug may interact with other drugs
stereoselectively (Crossley, 1995). For instance,
stereoselective interactions have been reported in man
between propranolol and calcium channel blockers,
cimetidine, and quinidine. Calcium channel blockers
nicardipine and diltiazem, and verapamil all decreased the
first pass metabolism of both enantiomers of propranolol.
However, this inhibitory effect was stereoselective for the
both R(+)-enantiomer in case of verapamil and nifedipine,
resulting in a significant increase in the (+) :(-) AUC ratios
in plasma. In terms of effects, nicardipine did not increase
the blood pressure reduction of propranolol, a phenomenon
that can be explained by a more significant
pharmacokinetic effect on the less active R(+)-enantiomer.
Similarly, cimetidine decreased the oral clearance of R(+)-
propranolol to a more significant degree than that of the
S(-)-enantiomer. As per quinidine human liver microsomes
studies indicated that selective inhibitor of CYPD26
reduced the ring hydroxylation propranolol in a
stereoselective manner in favour of R(+)-propranolol. This
was in agreement with in vivo studies showing 180% and
100% increases in the plasma AUCs of R(+)- and S(-)propranolol, respectively, because of quinidine coadministration. Interestingly, all these studies have shown
that the inhibition of the metabolism propranolol by
different drugs is stereoselective for R-(-)-propranolol
(Rezamehvar et al., 2001).
The pharmacokinetics of R – and S- atenolol after
intravenous administration of racemic atenolol were
studied in 3-, 12- and 24-month –old rats and 3-month-old
rats with renal failure induced by uranyl nitrate. In all age
groups, the area under the plasma concentration-time
curves is higher for R- than for S-atenolol; volume of
distribution, total clearance and renal clearance are lower
for R-atenolol than for S-atenolol , but the differences are
small. The total amount of both enantiomers excreted in
the urine is decreased in the rats with renal failure.
Therefore there is no stereoselective effect of treatment of
the rats with uranyl nitrate (Bogaert, 1993).
With pretreatment of rats with clofibrate, clinically
important interaction of clofibrate on the chiral disposition
of ibuprofen was observed. With respect to the protein
levels of two key enzymes involved in chiral inversion,
clofibrate pretreatment significantly induced expression of
long chain acyl-coenzyme a synthetase, although the
expression of the epimerase was unaltered. It is concluded,
that clofibrate may increase the proportion of R-ibuprofen
incorporated into long-lived lipid stores (Stefen scheuerer,
1998).
316
International Journal of Pharmaceutical Sciences and Nanotechnology
Significant differences in the protein binding and the
total systemic plasma clearance of (-) - and (+)-verapamil
in humans was observed (Eichelbaum et al., 1984). The
difference in clearance presumably was caused by hepatic
clearance, because oral administration resulted in
significantly higher concentrations of (+)-verapamil.
Pharmacokinetic studies of the enantiomers of
verapamil in rabbits and dogs proved that there were no
great differences in kinetics in the rabbit showing that each
enantiomer has similar qualitative effects, but with the (-)enantiomer showing greater potency. But the enantiomeric
differences in the dog were found due to the differences in
protein biding and metabolism which may resemble more
closely the situation in humans (Martine et al., 2004).
Conclusion
The increasing availability of a single enantiomer drugs
promises pharmaceutics scientists to formulate safer, better
tolerated, and more efficacious medications for treating
patients. When both a single enantiomer and a racemic
formulation of a drug are available, the information from
clinical trials and clinical experience should be used to
decide which formulation is most appropriate.
References
Agranat I, Caner H, and Caldwell J. Putting chirality to work: the
strategy of chiral switches. Nat. Rev. Drug Discov. 1(10):
753-768 (2002).
Balkovec JM, Dake GR, Fujimoto A, Koft ER, Niu D, Stork G,
and Tata JR. The First Stereoselective Total Synthesis of
Quinine. J. Am. Chem. Soc. 123: 3239-3242 (2001).
Chong E, and Ensom MH. Pharmacogenetics of the proton pump
inhibitors: a systematic review. Pharmacotherapy. 23(4):
460-471 (2003).
Christopher J, and Welch. Chiral chromatography in support of
pharmaceutical research. Journal of chromatography. 16: 1757 (2004).
Collins AN, Sheldrake GN, and Crosby J. Chirality in Industry.
Wiley, New York, 1992.
Conte U, Maggi E, De Lorenzi G, and Caccialanza. Evaluation of
stereoselective dissolution of verapamil hydrochloride from
matrix tablets press-coated with chiral excipients.
International Journal of Pharmaceutics. 136: 43-52 (1996).
Coughtrie MW, Ask B, Rane A, Burchell B, and Hume R. The
enantioselective glucuronidation of morphine in rats and
humans. J. Clin. Pharmacol. 38(19): 3273-3280 (1989).
Crossley R, Chirality and the Biological Activity of Drugs, CRC
Press, Boca Raton, 1995.
Eichelbaum M, Mikus G, and Vogelgesang B. Pharmacokkinetics
of (+)-, (-)- and (±) verapamil after intra venous
administration. J. Clin. Pharmacol. 17: 453-458 (1984).
Eichelbaum M, and Gross AS. Stereochemical aspects of drug
action and disposition, Advances in Drug Research,
Academic Press, London, 1996, pp. 1-64.
Eriksson T, Bjorkman S, and Hoglund P. Clinical pharmacology
of thalidomide. Eur. J. Clin. Pharmacol. 57(5): 365-76 (2001).
Volume 1 • Issue 4 • January-March 2009
Frans M, Belpaire, Rosseel M, Vermeulen, Frits DS, and Marc G.
Stereoselective Pharmacokinetics of atenolol in the rat:
Influence of aging and of renal failure. Mechanisms of Ageing
and Develpoment. 67: 201-210 (1993).
Friedman PA, and Zeidel ML. Victory at C. Nat. Med. 5(6): 620621 (1999).
Gatley SJ, MacGregor RR, Fowler JS, Wolf AP, Dewey SL, and
Schlyer DJ. Rapid stereoselective hydrolysis of (+)-cocaine in
baboon plasma prevents its uptake in the brain: implications
for behavioral studies. J. Neurochem. 54(2): 720-723 (1990).
Gristwood RW, and Greaves JL. Levobupivacaine: a new safer
long acting local anaesthetic agent. Inv. Drugs. 8: 861–876
(1999).
Gristwood RW. Cardiac and CNS toxicity of levobupivacaine:
strength of evidence for advantage over bupivacaine. Drugs
Saf. 25: 153–163 (2002).
Indra KR. Chirality In Drug Design And Development, Marcel
Dekker, New York, 2004.
Islam MM, Mahdi JG, and Bowen ID. Pharmacological
importance of stereochemical resolution of enantiomeric
drugs. Drug safety. 17: 149-165 (1997).
Liu W, and Ager. Handbook of Chiral Chemicals, Marcel
Dekker, New York. pp. 84-90 (1999).
Lorfen H, and Litold M. Enantio selective disposition of oral
amlodipine in healthy volunteers. Chirality. 6: 531-536
(1994).
Millership J, and Fitzpatrick A. Commonly used chiral drugs: a
survey. Chirality. 15: 573-576 (1993).
Martine E, Laethem, Frans M, Belpaire, Pascal, Wijnant, Marc G,
and Bogaert. Stereoselective Pharmacokinetics of oxprenolol,
propranolol and verapamil. Chirality. 7:616-622 (2004).
Meyring M, Muhlbacher J, Messer K, Kastner-Pustet N,
Bringmann G, Mannschreck A, and Blaschke G. In vitro
biotransformation of (R)- and (S)-thalidomide: application of
circular dichroism spectroscopy to the stereochemical
characterization of the hydroxylated metabolites. Anal. Chem.
74(15): 3726-35 (2002).
Nowak R, Single-isomer Levalbuterol: A Review of the Acute
Data. Current Allergy and Asthma Reports. 3: 172-178
(2003).
Olsen GD, Wendel HA, Livermore JD, Leger RM, Lynn RK, and
Gerber N. Clinical effects and pharmacokinetics of racemic
methadone and its optical isomers. Clin. Pharmacol. Ther.
21(2): 147-157 (1977).
Rezamehvar, Dion R, Brocks. Stereospecific pharmacokinetics
and pharmacodynamics of beta adrenergic blockers in
humans. journal of pharmaceutical science. 4: 185-200
(2001).
Stinson S. Counting on chiral drugs. Chem. Eng. News. 76:
83-103 (1998).
Sheldon RA. Chirotechnology. Marcel Dekker, New York, 1993,
p. 166.
Sheldon R.A. Chirotechnology. Marcel Dekker, New York, 1999,
p. 188.
Stefen S. Effect of Clofibrate on the Chiral disposition of
ibuprofen in rats. The Journal of Pharmacology and
Experimental Therapeutics. 284: 1132-1138, (1998).