Comparative pharmacology of S(+)-ibuprofen and (RS)-ibuprofen.
Racemic ibuprofen, which contains equal quantities of R(-)-ibuprofen and S(+)-ibuprofen, has been used as an anti-inflammatory and analgesic agent for over 30 years. Although the S(+)-enantiomer is capable of inhibiting cyclooxygenase (COX) at clinically relevant concentrations, R(-)-ibuprofen is not a COX inhibitor. The two enantiomers of ibuprofen are therefore different in terms of their pharmacological properties and may be regarded as two different 'drugs'. They also differ in terms of their metabolic profiles. For example, R(-)-ibuprofen becomes involved in pathways of lipid metabolism and is incorporated into triglycerides along with endogenous fatty acids. S(+)-Ibuprofen does not appear to become involved in these unusual metabolic reactions, which is why S(+)-ibuprofen is regarded as being metabolically 'cleaner' than racemic ibuprofen. When racemic ibuprofen is given to humans, a substantial fraction of the dose of R(-)-ibuprofen (50%-60%) undergoes 'metabolic inversion' to yield S(+)-ibuprofen. On this basis, it has been argued that to obtain clinical effects that are comparable to those of a given dose of racemic ibuprofen, the dose of S(+)-ibuprofen would need to be about 75% of the dose of the racemate. However, this 'pharmacokinetic' rationale does not take into account the fact that inversion is not instantaneous, that there is variability in the extent of inversion between individuals, and that the kinetics of inversion may differ depending on the dosing situations. For example, the extent of inversion appears to be reduced when the racemate is given to patients experiencing acute pain. Recent studies have demonstrated that the clinical benefits of racemic ibuprofen can be derived from the administration of the single S(+)-enantiomer at a dose that is half that of the racemate. For example, 200 mg of S(+)-ibuprofen has been found to be superior or at least equivalent to 400 mg of the racemate in the relief of dental pain. Possible explanations for this higher than expected efficacy of S(+)-ibuprofen are considered.
Evans
A M
AM
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide. allan.evans@unisa.edu.au
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen