Protein Binding as a Primary Determinant of the Clinical Pharmacokinetic Properties of Non-Steroidal Anti-Inflammatory Drugs

Abstract

The ability of a wide variety of anionic, cationic, and neutral drugs to bind in a reversible manner to plasma proteins has long been recognised. Non-steroidal anti-inflammatory drugs (NSAIDs) are distinguished as a class by the high degree to which they bind to plasma protein. Plasma protein binding properties are primary determinants of the pharmacokinetic properties of the NSAIDs. Theoretical relationships are reviewed in order to define quantitatively the impact of plasma protein binding on clearance, half-life, apparent volume of distribution, and the duration and intensity of pharmacological effect. The quantitative relationships governing competitive displacement binding interactions are also presented. Experimental methods for in vitro and in vivo determination of the degree of plasma protein binding are discussed. The more common in vitro methods are equilibrium dialysis and ultrafiltration. Methods for characterising the degree of plasma protein binding in vivo consist of either measuring the concentration of drug at equilibrium in an implanted semipermeable vessel or measuring the relative drug concentrations in two body spaces with different protein content. Emphasis is given to the comparative advantages and disadvantages of experimental application of the various in vitro and in vivo methods. Plasma protein binding is discussed as a determinant of the trans-synovial transport of NSAIDs. Trans-synovial transport of NSAIDs appears to be a diffusional process. Limited data in humans receiving ibuprofen, indomethacin, aspirin, carprofen, alclofenac, or diclofenac suggest that clearance of each of these NSAIDs from the synovium is slower than clearance from plasma. The clinical data relevant to the relationship between plasma NSAID concentration and various measures of anti-inflammatory effect are reviewed. A positive correlation between plasma NSAID concentration and anti-inflammatory effect has been observed in only one study on naproxen and one study on piroxicam. In several other studies, the lack of concentration-response correlations is generally attributed to the relatively subjective, quantitatively inexact methods used to assess anti-inflammatory effect and analgesia in arthritic patients, as well as the substantial interpatient variabilities in the fraction of unbound NSAID and the unbound plasma NSAID concentration. In view of the generally poor correlation between concentration and therapeutic response, routine therapeutic monitoring of total plasma NSAID concentration is not recommended as a means of titrating individual dosages to the desired effect in each patient.(ABSTRACT TRUNCATED AT 400 WORDS)

Stereoselective disposition of flurbiprofen in normal volunteers.

“…the complete bioavailability of racemic flurbiprofen reported previously, this conclusion is not surprising (Risdall et al, 1978;Szpunar et al, 1987). The low systemic clearance of the arylpropionic acids suggests that intrinsic (unbound) clearance and fraction unbound may be the primary determinants of systemic clearance (Lin et al, 1987;Tozer, 1981;Williams, 1990). The data in Table 1 indicate that the significantly greater clearance of R-compared with Sflurbiprofen disappears when unbound clearances are compared.…”

“…Therefore, for this particular pair of enantiomers, the difference in systemic clearances may be explained by enantioselectivity in plasma protein binding. The fraction unbound may also influence the apparent volume of distribution but to a limited degree for drugs such as flurbiprofen which are essentially restricted to the extracellular space (Lin et al, 1987;Tozer, 1981). The latter is reflected in the slightly but not significantly greater steady-state volume of distribution of the less highly bound R-enantiomer.…”

“…Flurbiprofen does not appear to undergo enantiomeric inversion in humans and is eliminated predominantly through the formation of oxidation products and acyl glucuronides Risdall et al, 1978;Szpunar et al, 1987) as indicated in Figure 1. In common with most arylpropionic acids, flurbiprofen is characterized by a relatively low clearance and volume of distribution; plasma protein binding and intrinsic clearance may therefore be expected to be primary determinants of its disposition (Lin et al, 1987;Szpunar et al, 1987). We have previously noted that on average the S-enantiomer is more highly bound than the R-isomer and that considerable interindividual variability in the enantiomeric binding ratio occurs .…”

Stereoselective disposition of flurbiprofen in uraemic patients.

“…Flurbiprofen, and most of the 2-arylpropionic acid nonsteroidal anti-inflammatory drugs are characterized by a low systemic clearance and a small volume of distribution, and therefore their disposition is sensitive to changes in plasma protein binding which is usually extensive (Lin et al, 1987;Risdall et al, 1978). The uraemic patients of this study exhibited a modest but significant degree of enantioselectivity in both oral clearance and volume of distribution which disappeared when unbound drug concentrations were considered (Tables 2 and 4).…”

Binding of endothelin to plasma proteins and tissue receptors: effects on endothelin determination, vasoactivity, and tissue kinetics

“…plasma clearance of exogenous or endogenous peptide are to be expected [17]. In rat plasma, binding of both ET-1 and big ET-I was higher than in human plasma, a species difference observed previously with a variety of drugs and endogenous substances.…”