`Clin Rheumatol (2001) (Suppl 1):S9—S14 Clin Rheumatol (2001) (Suppl 1):S9—S14
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`©. 2001 Clinical Rheumatology ©. 2001 Clinical Rheumatology
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`Clinical Clinical
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`Rheumatology Rheumatology
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`
`
`Comparative Pharmacology of S(+)-Ibuprofen and (RS)-Ibuprofen Comparative Pharmacology of S(+)-Ibuprofen and (RS)-Ibuprofen
`
`
`A. M. Evans A. M. Evans
`
`School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia
`
`
`Abstract: Racemic ibuprofen, which contains equal Abstract: Racemic ibuprofen, which contains equal
`
`quantities of R(-)-ibuprofen and S(+)-ibuprofen, has quantities of R(-)-ibuprofen and S(+)-ibuprofen, has
`
`been used as an anti-inflammatory and analgesic agent been used as an anti-inflammatory and analgesic agent
`
`for over 30 years. Although the S(+)-enantiomer is for over 30 years. Although the S(+)-enantiomer is
`
`capable of inhibiting cyclooxygenase (COX) at clinically capable of inhibiting cyclooxygenase (COX) at clinically
`
`relevant concentrations, R(-)-ibuprofen is not a COX relevant concentrations, R(-)-ibuprofen is not a COX
`
`inhibitor. The two enantiomers of ibuprofen are there-inhibitor. The two enantiomers of ibuprofen are there-
`
`fore different in terms of their pharmacological proper-fore different in terms of their pharmacological proper-
`
`ties and may be regarded as two different `drugs'. They ties and may be regarded as two different `drugs'. They
`
`also differ in terms of their metabolic profiles. For also differ in terms of their metabolic profiles. For
`
`example, R(-)-ibuprofen becomes involved in pathways example, R(-)-ibuprofen becomes involved in pathways
`
`of lipid metabolism and is incorporated into triglycerides of lipid metabolism and is incorporated into triglycerides
`
`along with endogenous fatty acids. S(+)-Ibuprofen does along with endogenous fatty acids. S(+)-Ibuprofen does
`
`not appear to become involved in these unusual not appear to become involved in these unusual
`
`metabolic reactions, which is why S(+)-ibuprofen is metabolic reactions, which is why S(+)-ibuprofen is
`
`regarded as being metabolically `cleaner' than racemic regarded as being metabolically `cleaner' than racemic
`
`ibuprofen. When racemic ibuprofen is given to humans, ibuprofen. When racemic ibuprofen is given to humans,
`
`a substantial fraction of the dose of R(-)-ibuprofen a substantial fraction of the dose of R(-)-ibuprofen
`
`(50%-60%) undergoes `metabolic inversion' to yield (50%-60%) undergoes `metabolic inversion' to yield
`
`S(+)-ibuprofen. On this basis, it has been argued that to S(+)-ibuprofen. On this basis, it has been argued that to
`
`obtain clinical effects that are comparable to those of a obtain clinical effects that are comparable to those of a
`
`given dose of racemic ibuprofen, the dose of S(+)-given dose of racemic ibuprofen, the dose of S(+)-
`
`ibuprofen would need to be about 75% of the dose of the ibuprofen would need to be about 75% of the dose of the
`
`racemate. However, this `pharmacokinetic' rationale racemate. However, this `pharmacokinetic' rationale
`
`does not take into account the fact that inversion is not does not take into account the fact that inversion is not
`
`instantaneous, that there is variability in the extent of instantaneous, that there is variability in the extent of
`
`inversion between individuals, and that the kinetics of inversion between individuals, and that the kinetics of
`
`inversion may differ depending on the dosing situations. inversion may differ depending on the dosing situations.
`
`For example, the extent of inversion appears to be For example, the extent of inversion appears to be
`
`reduced when reduced when
`
`the racemate the racemate
`
`is given is given
`
`to patients to patients
`
`experiencing acute pain. Recent studies have demon-experiencing acute pain. Recent studies have demon-
`
`strated that the clinical benefits of racemic ibuprofen strated that the clinical benefits of racemic ibuprofen
`
`can be derived from the administration of the single can be derived from the administration of the single
`
`
`Correspondence and offprint requests lo: Associate Professor A.M Correspondence and offprint requests lo: Associate Professor A.M
`
`Evans, School of Pharmacy and Medical Sciences, University of Evans, School of Pharmacy and Medical Sciences, University of
`
`South Australia, North Terrace, Adelaide 5000, South Australia. South Australia, North Terrace, Adelaide 5000, South Australia.
`
`E-mail: allan.evans@unisa.edu.au E-mail: allan.evans@unisa.edu.au
`
`
`S(+)-enantiomer at a dose that is half that of the S(+)-enantiomer at a dose that is half that of the
`
`racemate. For example, 200 mg of S(+)-ibuprofen has racemate. For example, 200 mg of S(+)-ibuprofen has
`
`been found to be superior or at least equivalent to 400 been found to be superior or at least equivalent to 400
`
`mg of the racemate in the relief of dental pain. Possible mg of the racemate in the relief of dental pain. Possible
`
`explanations for this higher than expected efficacy of explanations for this higher than expected efficacy of
`
`S(+)-ibuprofen are considered. S(+)-ibuprofen are considered.
`
`
`Keywords: Chirality; Cyclooxygenase; Enantiomers; Keywords: Chirality; Cyclooxygenase; Enantiomers;
`
`Ibuprofen; Non-Steroidal Anti-Inflammatory Drugs; Ibuprofen; Non-Steroidal Anti-Inflammatory Drugs;
`
`Pharmacokinetics Pharmacokinetics
`
`
`
`Introduction Introduction
`
`
`If an object is symmetrical, then the mirror image of that If an object is symmetrical, then the mirror image of that
`
`object is spatially identical to the original. This is not the object is spatially identical to the original. This is not the
`
`case for an asymmetrical object (one that cannot be case for an asymmetrical object (one that cannot be
`
`divided into two identical halves). Try placing your divided into two identical halves). Try placing your
`
`right-hand into a left-handed glove, and you will right-hand into a left-handed glove, and you will
`
`immediately understand the importance of asymmetry immediately understand the importance of asymmetry
`
`in everyday life. Handedness, or chirality, also exists in in everyday life. Handedness, or chirality, also exists in
`
`the structure of organic molecules — usually in the form the structure of organic molecules — usually in the form
`
`of a tetrahedral carbon atom covalently linked to four of a tetrahedral carbon atom covalently linked to four
`
`different substituents. A molecule containing one chiral different substituents. A molecule containing one chiral
`
`carbon atom can exist as two non-superimposable carbon atom can exist as two non-superimposable
`
`mirror-image forms, or enantiomers. As the number of mirror-image forms, or enantiomers. As the number of
`
`chiral carbon atoms within a molecule increases, so too chiral carbon atoms within a molecule increases, so too
`
`does the number of stereoisomers. About 50% of all does the number of stereoisomers. About 50% of all
`
`medicinal drugs used by humans contain an element of medicinal drugs used by humans contain an element of
`
`chirality within their chemical structure, and can chirality within their chemical structure, and can
`
`therefore exist of two or more stereoisomers. About therefore exist of two or more stereoisomers. About
`
`half of these (about 25% of all drugs) are actually used half of these (about 25% of all drugs) are actually used
`
`as mixtures of these stereoisomers — that is, as racemic as mixtures of these stereoisomers — that is, as racemic
`
`mixtures [1]. An example of such a drug is ibuprofen, mixtures [1]. An example of such a drug is ibuprofen,
`
`which contains a single chiral carbon atom within its which contains a single chiral carbon atom within its
`
`propionic acid side chain (Fig. 1). The two individual propionic acid side chain (Fig. 1). The two individual
`
`enantiomers of the molecule are referred to as R(-)-enantiomers of the molecule are referred to as R(-)-
`
`MYLAN EXHIBIT - 1066
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd.
`IPR2022-00722
`
`

`

`10
`
`Chiral carbon atom
`
`CH3
`H C-CH2
`CH3
`
`CH3
`c-cooH
`H
`
`Fig. I. Chemical structure of ibuprofen, showing the position of the
`single chiral carbon atom. Thu enantiomer with the S configuration at
`this carbon atom is an inhibitor of COX-1 and COX-2, whereas the
`mirror-image R form is not capable of inhibiting either enzyme at
`clinically relevant concentrations.
`
`ibuprofen and S(+)-ibuprofen. For the past 30 years, the
`drug has been used primarily as an equal mixture of
`these two enantiomers. However, enantiomerically pure
`preparations of the S(+)-enantiomer are becoming
`available in an increasing number of countries.
`
`Chirality and Pharmacology
`
`Molecular chirality can be extremely important in the
`interactions between drug molecules and biological
``receptors'. This is because most biological receptors
`(enzymes, transporters, membrane proteins etc.) are
`themselves made up of chiral molecules. Therefore,
`receptors can often discriminate between the enantio-
`mers of a chiral drug, and as a consequence the
`individual enantiomers of a chiral drug can differ
`enormously
`in
`their effects on
`the body (their
`pharmacological and toxicological effects). Because
`enantiomers can also differ in their interactions with
`plasma proteins, liver enzymes and renal transporters,
`they can also differ significantly in terms of their
`pharmacokinctic properties.
`Until 1984, the chirality of drug molecules was
`something that was considered primarily by medicinal
`chemists and experimental pharmacologists. In that year,
`a. landmark article entitled `Stereochemistry, a Basis for
`Sophisticated Nonsense in Pharmacokinetics and Clin-
`ical Pharmacology' was published in the European
`Journal of Clinical Pharmacology [2]. This paper
`questioned why racemic drugs were being used when,
`in many cases, the individual enantiomers elicited
`completely different pharmacological properties. A
`flurry of papers on the `single enantiomer versus
`racemate' debate followed, and a number of drugs that
`were previously marketed in their racemic forms were
`subsequently made available as enantiomerically pure
`preparations. Regulatory agencies also developed guide-
`lines for the registration of chiral drugs, including the
`registration of a single enantiomeric version of an
`approved racemic drug.
`Although ibuprofen has been used as a chiral drug
`since its introduction over 30 years ago, there has been a
`
`the pharrnacokinetic and
`in
`interest
`long-standing
`pharmacodynamic properties of its individual enantio-
`mers, as reviewed in recent years [3-5].
`
`A. M. Evans
`
`Pharmacodynamic Effects of Ibuprofen — the
`Role of Chirality
`
`NSAIDs appear to exhibit most of their pharmacological
`effects by inhibition of the cyclooxygenase-mediated
`transformation of arachidonic acid to thromboxane and
`the various prostaglandins [4,6-8]. For the profen class
`of NSAIDs, including ibuprofen, naproxen and ketopro-
`fen, the S-enantiomers are effective
`inhibitors of
`cycloxygenase (COX forms 1 and 2) in vitro and elicit
`analgesic and anti-inflammatory effects in vivo. Because
`the R-enantiomers do not inhibit prostaglandin synthesis,
`one might expect that they would also be ineffective as
`analgesic and anti-inflammatory agents
`in vivo.
`Although this is true for some of the profens, ibuprofen
`and fenoprofen represent two notable examples in which
`this general rule does not hold. In both of these cases, the
`R-enantiomers undergoes extensive enzyme-mediated
``chiral inversion' in experimental animals [6,9,10] —
`effectively, the body transforms some of the `1Z-isomer'
`to the `S-isomer'. Therefore, when the R(-)-isomer of
`ibuprofen was tested for pharmacological activity in
`experimental animal models, it was found to share the
`analgesic, antiinflammatory and antipyretic effects of
`S(+)-ibuprofen [11].
`In addition to reducing the synthesis of prostaglandins
`via inhibition of COX-1 and COX-2, ibuprofen and other
`NSAIDs elicit COX-independent biological actions,
`including an ability to suppress neutrophil attraction
`and activation, uncouple oxidative phosphorylation, and
`inhibit the mitochondrial oxidation of fatty acids. These
`and other COX-independent actions are invariably
`exerted non-enantioselectively — that is, both enantio-
`mers have similar potency, as reviewed previously [4-6].
`Ilowever, the contribution of these effects to the clinical
`efficacy and tolerability of ibuprofen and other NSAIDs
`is still unknown. As described below, a number of
`clinical efficacy studies have shown that S(+)-ibuprofen
`is as effective as racemic ibuprofen despite being taken
`at half the dose of the racemate. This in itself is indirect
`evidence that the contribution of the non-enantioselec-
`tive COX-independent actions of the R(-)-enantiomer
`are unlikely to be important determinants of the drugs'
`efficacy.
`
`Pharmacokinctics of R(-) and S(+)-Ibuprofen
`
`The pharmacokinetics features of R(-)- and S(+)-
`ibuprofen, together with parameters describing simila-
`rities and differences between the enantiomers, are
`summarised in Table 1. Although there are minor
`differences between the pharmacokinetics of the en-
`antiomers (the R(-)-isomer is more tightly bound to
`plasma proteins and has a shorter half-life etc.), the most
`
`

`

`Pharmacology of S(+)-Ibuprofen
`
`Table 1. Pharmacokinetic properties of ibuprofen enantiomers [2,4,6)
`
`11
`
`General property
`
`Parameter values
`
`Absorption
`
`Distribution
`
`Clearance
`
`Route of elimination
`
`Half-life
`
`Extensive; rapid for conventional products; rate but
`not extent influenced by food
`
`The enantiomers distribute extravascularly but have
`small volumes of distribution due to extensive binding
`to plasma albumin
`Slow distribution into and out of synovial fluid and
`CSF due in part to extensive plasma protein binding
`Mainly hepaiically cleared; low hepatic extraction
`ratio and a clearance which is low relative to liver
`blood flow
`Almost exclusively metabolic, by glucuronidation and
`oxidation. Large % of dose recovered as metabolites
`in urine. Minimal reliance on biliary excretion
`R(-)-ibuprofen undergoes metabolic chiral inversion
`and incorporation into triglycerides, whereas S(+)-
`ibuprofen does not
`Short half-life, requiring 3-4 doses per day in chronic
`conditions
`
`Bioavailability of both enantiomers is about 100%;
`absorption half-life is about 30 min after conventional
`dose forms
`Both enantiomers have a volume of distribution of
`about 10-121
`
`The fraction unbound in plasma is 0.008 for S(+)-
`ibuprofen and 0.004 for R(-)-ibuprofen
`Plasma clearance about 50-150 inlimin for both
`enantiomers
`
`Greater than 90% recovery of oral dose in urine as
`metabolites, mainly oxidation products and their
`glucuronide metabolites
`
`Both enantiomcrs have a half-life of 2 hours in healthy
`adults. In some studies, the R(.)-enantiomer has a
`shorter half-life that S(+)-ibuprofen
`
`striking difference is in terms of their metabolic profiles.
`These differences arise primarily from the ability of
`R(-)-ibuprofen, but not S(+)-ibuprofen, to form a
`thioester with coenzyme A — this allows the R(-)-
`enantiomer to undergo inversion of configuration and
`become involved in the pathways of lipid metabolism
`[4,6,7,9,10].
`The first important metabolic feature that distin-
`guishes R(-)-ibuprofen from its minor-image form is
`its ability to undergo metabolic chiral inversion. This
`process is clinically important because it produces a
`COX-inhibitor from a non-COX-inhibiting precursor. In
`humans, the fraction of a dose of R(-)-ibuprofen that
`is inverted to S(+)-ibuprofen is, on average, 50-60%
`[12-15]. However, the extent of chiral inversion varies
`between individuals — for example, in oSteoarthritis
`patients being treated with racemic ibuprofen, the
`fractional inversion of R(-)-ibuprofen varied between
`35% and 85% [13].
`Factors that have been suggested or demonstrated to
`influence the chiral inversion of R(-)-ibuprofen after
`dosing with the racemate include formulation type
`[16,17], disease state [18] and other drugs [19].
`However, part of the difficulty in investigating the
`variability in fractional inversion (FI) is that that the
`measurement of FI requires the use of pseudoracemates
`[19], full characterisation of the urinary metabolites [13],
`or the separate administration of the individual en-
`antiomers [14,15]. Even then, saturable plasma protein
`binding and pharmacokinetic interactions between the
`enantiomers can compromise the validity of the Fl
`estimates [6,15].
`Recently, Jamali and Kunz-Dober [18] suggested that
`the chiral inversion of R(-)-ibuprofen was reduced when
`racemic ibuprofen was given to humans after dental
`
`surgery. Evidence leading to this suggestion was a
`reversal in the enantiomeric ratio of the drug in plasma —
`prior to surgery, the mean area-under-the-curve value for
`that of R(-)-
`in plasma exceeded
`S(+)-ibuprofen
`ibuprofen, whereas in the same subjects after oral
`surgery the mean area under the curve for the S(+)-
`enantiomer was lower than that of R(-)-ibuprofen.
`However, any speculation regarding the extent of
`chiral inversion of R(-)-ibuprofen, from data obtained
`after dosing with racemic ibuprofen, relies on the
`validity of certain assumptions that need to be made
`regarding other pharmacokinetic parameters, such as
`clearance of the enantiomers by non-inversion routes
`[16].
`The second important feature that distinguishes R(-)-
`ibuprofen from S(+)-ibuprofen is its ability to interfere
`with normal lipid metabolism. In rats, the formation of
`hybrid triglycerides containing ibuprofen in place of
`endogenous fatty acids has been demonstrated after
`dosing with R(-)ibuprofen but not S(+)-ibuprofen [20].
`These `hybrid triglycerides' were deposited in adipose
`tissue, forming long-lasting reservoirs from which the
`drug was slowly released. At present the clinical
`consequences of the participation of the R-enantiomers
`of ibuprofen and other profens in lipid metabolism are
`unknown.
`The enantiomers of ibuprofen are metabolised by
`the metabolites undergoing
`oxidative routes, with
`subsequent glucuronidation, to varying extents, prior to
`excretion [12,13]. When racemic ibuprofen is adminis-
`tered, the number of metabolites that are produced is far
`greater that that expected from dosing with the S(+)-
`enantiomer alone [4], as shown in Fig. 2. However,
`there is no compelling evidence that the metabolites of
`R(-)-ibuprofen (other than S(+)-ibuprofen) contribute to
`
`

`

`12
`
`A. M. Evans
`
`Carboxy-R-ibuprofen
`Hydroxy-R-ibuprofen
`Acyl Glucuronides
`
`Carboxy-S•lbuprofet
`Hydroxy-S-ibuprofen
`Acyl Glucuronides
`
`R-ibuprofen-
`glucuronide 4*"' R(-)-ibuprofen
`
`R-ibuprofen-00A
`
`S-ibuprofen-
`SH-ibuprofen gsftik` glucuronide
`-$00'
`
`''''''A5os-ntaccy"atwxzwv3-004-s'
`S-ibuprofen-CoA
`
`Hybrid triglycerides incorporating ibuprofen
`
`Fig. 2. Metabolic profile of R(-)- and S(+)-ibuprofen after administration of the racemate. The encircled area shows the metabolic profile of S(+)-
`ibuprofen when it is administered as the single enantiomer. The chiral inversion of R(-)-ibuprofen occurs via the formation of a thioester with
`coenzyme A (R-ibuprofen-CoA intermediate). This intermediate also serves to introduce R(-)-ibuprofen into the pathways of lipid metabolism,
`resulting in the formation of `hybrid triglycerides' in which the ibuprofen moiety rakes the place of an endogenous fatty acid.
`
`the toxic effects of the racemate. The enantiomers of
`ibuprofen and their metabolites form acyl glucuronides —
`these metabolites are characterised by an ester linkage
`between the carboxylic acid functional group of a drug
`and glucuronic acid. The ability of acyl glucuronides to
`bind to endogenous macromolecules such as albumin is
`well established, and there is some evidence that these
`drug—protein adducts may be involved in causing
`potentially serious hypersensitivity reactions [21-24].
`For drugs that do form acyl glucuronides, the extent of
`drug—protein adduct formation is related to the exposure
`to the glucuronide conjugate, and for this reason there
`may be an increased propensity for binding to proceed in
`the organs of glucuronide formation (liver) and excretion
`(kidney), both of which are potential sites of NSAID
`toxicity [23]. Although ibuprofen—protein adducts have
`been detected in humans taking RS-ibuprofen [25] the
`relative propensity for the individual isomers to form
`these adducts is unknown. Previously, it was suggested
`that the use of ibuprofen as an enantiomerically pure
`preparation of the S(+)-enantiomer has the capacity to
`reduce the formation of protein—drug adducts [4].
`
`Studies Comparing S(+)-Ibuprofen and
`Racemic Ibuprofen
`
`Surprisingly, there are very few published studies that
`have actually compared the clinical efficacy of S(+)-
`ibuprofen and the racemate in prospective trials. Dionne
`and McCullagh [26] compared the relative efficacy of
`S(+)-ibuprofen and RS-ibuprofen in the oral surgery
`model of dental pain. This was a single-dose, double-
`blind, parallel group study in which subjects received
`
`treatment (200 mg of S(+)-ibuprofen, 400 mg of S(+)-
`ibuprofen, 400 mg of RS-ibuprofen or placebo) after
`surgical removal of a molar. It was reported that 400 mg
`of S(+)-ibuprofen provided better analgesic efficacy than
`400 mg of the racemate, and both drugs were superior to
`placebo. These results were not unexpected. However,
`200 mg of S(+)-ibuprofen provided a more rapid onset of
`analgesic action than 400 mg of the racemate and
`provided better pain relief over the first 3 h after dosing.
`This finding was unexpected in that, because of the
`inversion process, one would expect 400 mg of racemic
`ibuprofen to generate the equivalent of about 300 mg of
`S(+)-ibuprofen (i.e. 200 mg from the S(+)-isomer
`present within the racemate plus an additional 100 mg
`from inversion of the R(-)-isomer), and therefore a better
`clinical response. Similar findings were contained within
`a patent application for `onset-hastened analgesic
`effects' of S(+)-ibuprofen compared with `equivalent'
`doses of the racemate (EurOpean Patent Application
`88906506.6). Unfortunately, plasma concentration—time
`data were not obtained in these studies, and so a pure
`pharmacokinetic explanation for the unexpected findings
`(e.g. more rapid absorption of the S(+)-enantiomer when
`taken alone) cannot be excluded.
`Singer et al. [27] compared the efficacy of S(+)-
`ibuprofen (600 mg or 1200 mg/day) and racemic
`ibuprofen (2400 mg/day) in patients with osteoarthritis
`of the hip. Although this study did not include a placebo
`group, it was significant in that all three treatments
`provided a statistically significant improvement in the
`standard WOMAC osteoarthritis index (compared with
`baseline), and 1200 mg/day of S(+)-ibuprofen was
`demonstrated to be statistically equivalent to 2400 mg
`of the racemate. There were no differences between the
`
`

`

`Pharmacology of S(+)-Ibuprofen
`
`two forms of ibuprofen in terms of adverse drug
`reactions. The results from this study support the
`findings of an earlier meta-analysis comparing the
`efficacy of S(+)-ibuprofen and racemic ibuprofen in a
`variety of disease states [28]. Additional studies
`comparing the clinical efficacy and tolerability of RS-
`ibuprofen and S(+)-ibuprofen are provided
`in an
`accompanying paper [29].
`Because of the chiral inversion of R(-)-ibuprofen in
`humans, a 1200 mg dose of racemic ibuprofen and a 900
`mg dose of S(+)-ibuprofen would produce similar values
`for the area under the plasma concentration—time curve
`for the S(+)-enantiomer. Therefore, on theoretical
`grounds one would predict that a dose ratio (i.e. the
`ratio of the dose of S(+)-ibuprofen to that of the
`racemate) of about 0.75 would ensure equivalent clinical
`effectiveness between the two forms of the drug.
`However, as described above, those clinical studies
`that have compared the two forms of the drug actually
`suggest that a lower dose ratio (0.5) may suffice, at least
`in some instances [26-29].. It could be argued that the
`studies themselves were not capable of detecting small
`differences in efficacy between the treatments, or that all
`doses produced maximal effects, meaning that it would
`be impossible to distinguish statistically between the
`treatments. However, in both the dental-pain model and
`the osteoarthritis study a significant dose—effect relation-
`ship was found for S(+)-ibuprofen.
`An explanation for the apparent conflict between the
`theoretical and actual equivalent dose ratio of S(+)-
`ibuprofen to racemic ibuprofen may reside in the ability
`of R(-)-ibuprofen, as a component of the racemate, to
`reduce in some way the effectiveness of the S(+)-
`enantiomer. This interaction could conceivably arise via
`a phannacokinetic mechanism (e.g. if R(-)-ibuprofen
`reduced the entry of S(+)-ibuprofen into a site of action)
`or via an effect at the level of COX-1 or COX-2. For
`example, although R(-)-ibuprofen is itself an ineffective
`COX inhibitor, it might interfere with the ability of S(+)-
`ibuprofen to interact with either or both forms of the
`enzyme. It is interesting, therefore, that Rainsford [5]
`recently reported competition between the enantiomers
`in their effects on prostaglandin production in vitro.
`Indeed, it was suggested that inhibition of the binding of
`S(+)-ibuprofen to intestinal COX-1 by R(-)-ibuprofen
`might in some way contribute to the• good gastrointest-
`inal tolerance of racemic ibuprofen compared to other
`NSAIDs. Neupert and coworkers [30] also provided
`some data that may support the concept of competition
`between the enantiomers for COX. These workers tested
`the effects of ibuprofen enantiomers, ibuprofen race-
`mate, and the CoA thioesters of ibuprofen enantiomers
`on the activity of COX-1 (inhibition of thromboxane
`production by human platelets) and COX-2 (inhibition of
`LPS-stimulated prostaglandin production by monocytes
`in aspirin-inactivated blood). The IC50 value for
`inhibition of COX-2 by S(+)-ibuprofen was 1.6 µmolll,
`whereas the value for R(-)-ibuprofen was greater than
`250 µmol/I — this result confirms that S(+)-ibuprofen is
`an effective COX-2 inhibitor whereas R(-)-ibuprofen is
`
`13
`
`not. If it is assumed that R(-)-ibuprofen does not
`interfere with the
`inhibition of COX-2 by S(÷)-
`ibuprofen, then one would predict an 1050 value for
`the racemate of about 3.2 µmoUl (i.e. twice the value for
`S(+)-ibuprofen). Surprisingly, the reported IC50 value
`for the racemate was 46.7 moll' — more than 10 times
`higher than the expected value. In the case of COX-1,
`the reported IC50 values for R(-)-ibuprofen (34.9 µmoll
`I), S(+)-ibuprofen (2.1 µmol/l) and racemic ibuprofen
`(6.5 µmo1/1) are more in keeping with a lack of effect of
`the R(-)-enantiomer on the COX-1 inhibitory effects of
`the S(+)-isomer.
`These findings raise the intriguing possibility that
`R(-)-ibuprofen may in some way reduce the in vivo
`effects of S(+)-ibuprofen on COX-2, without altering its
`actions on COX-1. This is particularly relevant because
`the beneficial effects of the drug are likely to be
`mediated to a large extent by inhibition of COX-2.
`However, the results of Boneberg and colleagues [31],
`using human platelets (COX-1), rat mesangial cells
`(COX-2) and human purified COX-1 and COX-2
`enzymes, tend not to support competition between the
`enantiomers in vitro. The variability between
`the
`experimental results from different in vitro models of
`COX-1 and COX-2 illustrates one of the acknowledged
`difficulties in interpreting the derived IC50 values for
`these enzyme systems [32].
`The CoA thioesters of R(-)- and S(+)-ibuprofen are
`also capable of inhibiting COX-1 and COX-2 activity in
`it was suggested
`that these metabolic
`vitro, and
`intermediates might contribute to the clinical effects
`observed after administration of R(-)-ibuprofen (they are
`not formed after taking S(+)-ibuprofen) [30]. However,
`it is also conceivable that these metabolites may reduce
`the COX-inhibitory activity of S(+)-ibuprofen via
`competitive or non-competitive binding interactions. If
`this were the case, then the efficacy of S(+)-ibuprofen
`might be reduced by coadministration of the R(-)-isomer
`(i.e. by taking the racemate).
`
`Benefits of Single Enantiomers
`
`In 1992, and again in 1996, 1 identified a range of
`potential advantages of administering profens, including
`ibuprofen, as enantiomerically pure preparations of the
`S-enantiomers [4,6]. These advantages included: re-
`duced metabolic load, reduced chance of pharmacoki-
`netic
`interactions with other drugs, avoidance of
`involvement in lipid metabolism and of the pharmaco-
`kinetic variability
`that arises from
`the metabolic
`inversion of R(-)-ibuprofen, and prevention of adverse
`events that may arise from the COX-independent actions
`of R(-)-ibuprofen. In addition, it was suggested that
`patient acceptability could be improved through the use
`of smaller doses. At that time, potential interactions
`between R(-)- and S(+)-ibuprofen for COX-1 and COX-
`2 were not considered, and this issue requires further
`exploration. To this day, the advantages of using the
`single enantiomer remain largely theoretical, and results
`
`

`

`14
`
`of clinical studies with S(+)-ibuprofen suggest that it has
`a similar adverse event profile to the racemate [291.
`In terms of the `single enantiomer versus racemate'
`debate, there are some who argue that racemic ibuprofen
`is one of the most successful drugs ever developed, and
`that after 30 years of use there is no compelling reason to
`start using the single S(+)-enantiomer. Others would
`argue that any attempt to reduce the unnecessary
`metabolic burden imposed upon a patient (through
`exposure to inactive isomers) is admirable. They may
`also argue that, as a general rule, fixed drug combina-
`tions (which is what a racemate actually is) should not be
`encouraged clinically unless an advantage has been
`demonstrated. Although patients might derive benefits
`from R(-)-ibuprofen, as a component of the racemate, it
`is only after it is metabolically inverted to its companion
`enantiomer. Also, in order to derive this benefit, we rely
`on a metabolic pathway about which we know very little
`in terms of toxicological significance. The inversion is
`not instantaneous and varies in both rate and extent
`between people and, possibly, within a person. The
`impact of factors such as disease on the extent of
`inversion remains largely unexplored.
`
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`
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