SERUM-PROTEIN BINDING OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS - A COMPARATIVE-STUDY

The unbound fraction in serum, f(u), is a critical parameter in descri bing and understanding the pharmacokinetics of NSAIDs. We compared f(u ), for 6 different NSAIDs using ultrafiltration of pooled serum at pH 7.4 and 24C. Measurements covered a wide concentration range in order to define binding affinity and number of binding sites. HPLC was used to measure drug concentrations in serum and ultrafiltrate. Direct inje ction of ultrafiltrate and serum (diluted 250x) permitted quantitation down to approximately 70 nM for most of the NSAIDs, i.e., approximate ly 15-20 ng/ml. Assuming binding only to albumin, the data were fitted to a model of two classes of binding sites with dissociation constant s K1 and K2. The lowest K1 (highest affinity) was found with flurbipro fen, 0.0658 mu M, the highest with ketoprofen, 5.23 mu M, an 80-fold d ifference. At low drug concentrations, f(u) becomes virtually constant and approaches a lower limit, f(u)(min). The following f(u)(min) valu es were calculated: diclofenac 0.21%; fenoprofen 0.25%, flurbiprofen 0 .022%, ketoprofen 0.52%, naproxen 0.039%, and tolmetin 0.37%. Thus the least bound NSAID, ketoprofen, had a value 24-fold that of the most h ighly bound, flurbiprofen. The NSAIDs also differed widely with regard to the extent of variation in f(u) within the range of therapeutic co ncentrations, and hence with regard to their potential as displacers o f other drugs.