The pharmacokinetics of chiral non-steroidal anti-inflammatory drugs in synovial fluid and plasma

This research described the pharmacokinetics of free/unbound and total (bound plus unbound) enantiomers of two commonly prescribed non-steroidal anti-inflammatory drugs (NSAIDs: ketoprofen and ibuprofen) in the synovial fluid and plasma of patients with inflammatory and non-inflammatory joint disease. This was facilitated by the development of enantiomeric assays of sufficient sensitivity to enable the measurement of the very low levels of non-protein bound drug commonly encountered in plasma, and synovial fluid. The assays involved formation of a mixed anhydride of the drug with ethylchloroformate and subsequent conversion to an amide by reaction with optically active amphetamine. The subsequently formed diastereomers were separated by gas chromatography/mass spectrometry (GC-MS) using selected ion monitoring (SIM). The sensitivity limitations of previous assays (with regard to the intended clinical studies) for these two drugs were explored, and confirmed the benefits for use of deuterated internal standards of the respective parent NSAIDs in subsequent GC-MS assays of these drugs. A practical, speedy and economical means of synthesis of deuterated ketoprofen from its nondeuterated counterpart (for use as an internal standard), was developed. This method may be a process worthy of consideration in the synthesis of deuterated internal standards for future GC-MS assays of similar compounds. The current GC-MS assays were capable of quantifying ketoprofen (2ng/mL) and ibuprofen (3ng/mL) enantiomers from a 2004 sample of synovial fluid or plasma, which made them particularly suitable for clinical pharmacokinetic studies. The clinical studies were conducted in human volunteers with effusions into the knee. Patients were assessed for functional capacity and severity of disease before being given a single oral dose of either ketoprofen or ibuprofen. Synovial fluid and plasma levels of free/unbound and total (bound plus unbound) NSAID enantiomers were determined over 24 hours, after which a number of patients continued twice daily administration of either drug for up to six months. Chronic-dose patients maintained daily diaries and re-visited the centre at monthly intervals for clinical examination and similar determination of synovial fluid and plasma NSAID enantiomer levels (6-10 hours post morning dose). In the single dose studies, the pharmacokineties of total and unbound drug in ketoprofen patients (n = 10) and ibuprofen patients (n = 5) were examined in synovial fluid and plasma according to several different models (compartmental, non-compartmental and moment analysis). The synovial fluid models provided a convenient means for characterising the transfer of the enantiomers of these drugs to and from synovial fluid. The moment analysis used to derive one of the models in the current work proved particularly convenient in this respect, and did not require single or multi-compartmental assumptions common to the other classic models. The synovial fluid model that provided the poorest fit to the data was a previously developed model that used total (rather than free) plasma levels of these drugs to describe transfer of the enantiomers to and from synovial fluid. Pharmacokinetic parameters for ibuprofen enantiomers were generally comparable to the limited body of information able to be gleaned from previous studies. The mean plasma half lives for enantiomers of both NSAIDs were considerably longer than indicated by previous studies. This was most likely due to the combined effect of enhanced sensitivity of the assays and longer sample collection periods (24 hr instead of 12 hr). This may have facilitated a better portrayal of the terminal phase of the individual drug enantiomer concentration-time curves compared to previous studies. Consistent with former studies, there was a general trend for synovial fluid enantiomer levels of both drugs (though lower than corresponding plasma levels) to take longer to reach maxima, though once achieved, were shown to persist for a longer time after dosing than for plasma. This finding agreed with the often observed phenomena of these NSAIDs being usefully prescribed to patients on a twice daily basis, despite having relatively short plasma half lives. The disposition of total ketoprofen in synovial fluid was non-stereoselective, and in agreement with previous studies. However, an interesting finding in the current ketoprofen work was the significantly higher level of S(+)- relative to R(-)- enantiomer observed in unbound synovial fluid concentration-time profiles of study patients. A plausible explanation for this may be related to a greater binding affinity of the R enantiomer relative to the S enantiomer - a finding suggested by in an in-vitro study some ten years ago, but not observed in other subsequent studies. The chronic dose studies were conducted to evaluate some of the difficulties associated with attempts at correlating the concentration and rate of movement into and out of the joint with the clinical response or adverse effects experienced by the patient. Disparity between monthly clinical indicators, global efficacy ratings and pharmacokinetic parameters were highlighted, and add further weight to the argument that if a simple dose-response relationship in patients who use these agents were to exist, it may not be as straightforward as once thought.