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Chirally Pure Non-Steroidal
Anti-Inflammatory Drugs
Introduction
Chirality is defined as the geometric property of a rigid object
(like a molecule or drug) of not being super imposable with its
mirror image. Chirality is a property of matter found throughout
biological systems, from the basic building blocks of life such
as amino acids, carbohydrates, and lipids to the layout of the
human body. The two mirror images of a chiral molecule are
termed R and S enantiomers. Both enantiomers have the same
chemical composition and structure, but in chiral environments
such as the receptors and enzymes in the body, they can behave
differently. A racemate or a racemic mixture is a mixture
containing equal amounts of both enantiomers. In case of a
drug, the two enantiomers may have different pharmacokinetic
and pharmacodynamic properties. It is worth remembering the
following important comments in the European Journal Of Clinical
Pharmacology, 1984, 26, 663-8 : “Too often, and even without
it being noticed, data in the scientific literature on mixture of
stereoisomers, racemates, are presented as if only one compound
were involved.The neglect of stereochemical aspects of drug action
…. degrades many pharmacokinetic studies to expensive “highly
sophisticated pseudoscientific nonsense…..The development of
‘hybrid’ drugs, presented as a step forward in medicinal chemistry,
tends to be step backward in therapy.” Clearly, 50% impurity in
pharmaceuticals is not acceptable.
Chirality and NSAIDs
The NSAIDs have been intensively studied from the perspective
of stereoselectivity. For NSAIDs, it is the enantiomer possessing
the S configuration that almost exclusively possess the antiinflammatory/ analgesic activity while R enantiomers lacks such
activity1 and may have some different activity2-6. For example,
R-Flurbiprofen and R-Etodolac are undergoing development for
the potential treatment of Alzheimer’s disease2 and cancer3-6,
respectively. However, most of the NSAIDs are traditionally
administered as racemates except Naproxen which is available
as the single S enantiomer. In the following sections, new unichiral
NSAIDs- Dexketoprofen, Dexibuprofen and S-Etodolac- are
discussed.
Joy Philip, Trivandrum
Dexketoprofen S(+)Ketoprofen]
Trometamol
Racemic Ketoprofen is a 50:50 mixture of S(+)- and R(-)enantiomers7. Most or all COX inhibitory activity of Ketoprofen
is attributed to the S(+)-enantiomer (Dexketoprofen)8. The
R-enantiomer is 30 to 5000 times less potent as an inhibitor
of COX-1 and about 100 times less potent as an inhibitor of
COX-29. In addition, S-Ketoprofen less GI ulcerogenic potential as
compared to the racemic Ketoprofen. In fact, R-enantiomer may
contribute to the pathogenesis of intestinal ulcers10.
The absorption of S-enantiomer from racemic Ketoprofen and
Dexketoprofen trometamol has been found to be equivalent and
rapid11. The fast absorption could account for the suitability of
Dexketoprofen in the management of acute pain. Dexketoprofen
is effective at half the dose of racemate9,12. Several clinical trials
conducted with orally administered Dexketoprofen trometamol in
acute painful inflammatory conditions- dental pain, dysmenorrhea,
acute musculoskeletal injuries, renal colic, orthopedic surgeriesand chronic painful inflammatory conditions like osteoarthritis,
have confirmed its high analgesic potency and good tolerability
profile13-26. When compared to enantiomerically equivalent
doses of Ketoprofen, Dexketoprofen trometamol has shown
a comparable analgesic efficacy and tolerability13,16,17,19-21 but a
faster onset of action13,16. In addition, Dexketoprofen improves
the activity of opioid analgesics like Fentanyl35 and reduces the
opioid requirement24.
Salient features of Dexketoprofen
•
Most or all COX inhibitory activity of Ketoprofen is attributed to the S(+)-enantiomer (Dexketoprofen)
•
R-enantiomer is 30 to 5000 times less potent as an inhibitor
of COX-1 and about 100 times less potent as an inhibitor of
COX-2
•
Dexketoprofen is less ulcerogenic than the racemic Ketoprofen and R-Ketoprofen
Medicine Update 2010  Vol. 20
•
Dexketoprofen has faster absorption than racemate
•
Dexketoprofen has established efficacy and tolerability in
the treatment of acute and chronic painful conditions
•
Dexketoprofen has comparable analgesic efficacy and tolerability but a faster onset of action than Ketoprofen
Dexibuprofen [S(+)Ibuprofen]
Racemic Ibuprofen contains equal quantities of R(-)Ibuprofen
and S(+)Ibuprofen. R-Ibuprofen and Dexibuprofen differ in their
physicochemical, pharmacological and metabolic properties.
S-Ibuprofen or Dexibuprofen is the pharmacologically active
enantiomer of racemic Ibuprofen. Dexibuprofen is the S(+)
(dextrorotatory)-enantiomer of Ibuprofen and accounts for
virtually all pharmacodynamic (analgesic, anti-inflammatory,
antipyretic) activities of the racemic compound27,28. In vitro,
Dexibuprofen is over 100 times as potent as the R-enantiomer
as an inhibitor of prostaglandin biosynthesis27. In therapy, potential
advantages of Dexibuprofen over racemic Ibuprofen include
lesser toxicity, greater clinical efficacy and/or less variability in
therapeutic effects achieved, and easier dose optimization, all at
half the dose of Ibuprofen. Several clinical trials and post marketing
surveillance studies have been performed to elucidate the efficacy
and safety of Dexibuprofen29-33. The findings from these studies
demonstrate that Dexibuprofen is effective and very well tolerated
in patients with acute dental pain29 and chronic osteoarthritis
pain30.These effects are comparable to Diclofenac, Celecoxib and
enantiomerically equivalent dose of racemic Ibuprofen29-33.
shown better gastrointestinal tolerability when compared with
non-selective NSAIDs51. Etodolac possesses a more favorable
therapeutic index between anti-inflammatory effects and gastric
irritation as compared to other NSAIDs52,53. However, it is
the S-enantiomer of Etodolac that possesses almost all of the
anti-inflammatory activity while R-Etodolac is almost inactive.
S-Etodolac is 2.6 times more potent than the racemate and 100
times more potent than R-enantiomer54. Furthermore, S-Etodolac
achieves greater concentrations in synovial fluid than plasma
compared to R-Etodolac55. S-Etodolac rapidly attains the peak
plasma concentration and is rapidly cleared from plasma compared
to R-Etodolac. R- and S-Etodolac competitively interact with each
other for binding to human serum albumin and are displaced by
each other56. In an open label, multicentric, comparative clinical
trial in 108 Indian patients with osteoarthritis, it was found that
S-Etodolac extended release 300 mg tablet was equally effective
in improving pain, stiffness and physical function when compared
to Etodolac extended release 600 mg tablet57. Both the drugs
were very well tolerated in this study. Thus, it is justified to use
a single active, potent enantiomer with the anti-inflammatory
activity i.e. S-Etodolac.
Salient features of S-Etodolac
•
S-enantiomer of Etodolac possesses almost all of the antiinflammatory activity while R-Etodolac is almost inactive
•
S-Etodolac is 2.6 times more potent than the racemate and
100 times more potent than R-enantiomer
•
S-Etodolac achieves greater concentrations in synovial fluid
than plasma
Salient features of Dexibuprofen
•
Dexibuprofen is the pharmacologically active enantiomer of
racemic Ibuprofen
•
S-Etodolac has a favorable pharmacokinetic profile compared to R-Etodolac.
•
Dexibuprofen is over 100 times as potent as the R-enantiomer
•
Efficacy and tolerability of S-Etodolac is comparable to the
racemate
•
Dexibuprofen has lesser toxicity, greater clinical efficacy,
less variability in therapeutic effects achieved and easier
dose optimization, all at half the dose of Ibuprofen
Conclusion
•
Dexibuprofen is effective and very well tolerated in patients
with osteoarthritis and dental pain
•
Efficacy comparable to Diclofenac, Celecoxib and double
dose of racemic Ibuprofen
S(+)Etodolac
S-Etodolac is a chirally pure, pharmacologically active form of
Etodolac containing only S(+)enantiomer.The racemate Etodolac
has analgesic, antipyretic, and anti-inflammatory properties34
with more selectivity for induced COX-2 (associated with
inflammation) over COX-1 (cytoprotective)35. Numerous studies
have established the efficacy and tolerability of racemic Etodolac
compared to other NSAIDs in the treatment of osteoarthritis,
rheumatoid arthritis and post-operative pain34,36-50. Etodolac has
838
The NSAIDs used in clinical practice contain both R and S
enantiomers, which have different pharmacological properties.
Since, it is the S-enantiomer that has the anti-inflammatory/
analgesic activity while R-enantiomer lacks such activity, it is thus
imperative to perform the chiral switch i.e. to develop only the
therapeutically effective S-enantiomer.This avoids the use of 50%
impurity in the form of R-enantiomer and thus provides a less
complex pharmacokinetics, avoids the enantiomer interactions
and reduces the metabolic load on the body.The development of
Dexketoprofen, Dexibuprofen and S-Etodolac is certainly a step
forward in this direction.
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