Serum protein binding of nonsteroidal antiinflammatory drugs: a comparative study.
The unbound fraction in serum, fu, is a critical parameter in describing and understanding the pharmacokinetics of NSAIDs. We compared fu 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 injection of ultrafiltrate and serum (diluted 250 x) permitted quantitation down to approximately 70 nM for most of the NSAIDs, i.e., approximately 15-20 ng/ml. Assuming binding only to albumin, the data were fitted to a model of two classes of binding sites with dissociation constants K1 and K2. The lowest K1 (highest affinity) was found with flurbiprofen, 0.0658 microM, the highest with ketoprofen, 5.23 microM, an 80-fold difference. At low drug concentrations, fu becomes virtually constant and approaches a lower limit, fumin. The following fumin values 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 highly bound, flurbiprofen. The NSAIDs also differed widely with regard to the extent of variation in fu within the range of therapeutic concentrations, and hence with regard to their potential as displacers of other drugs.
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Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA.
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D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood* / Q000493:pharmacokinetics; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D004008:Diclofenac / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005279:Fenoprofen / Q000097:blood / Q000493:pharmacokinetics; D005480:Flurbiprofen / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007660:Ketoprofen / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000097:blood / Q000493:pharmacokinetics; D011485:Protein Binding; D014046:Tolmetin / Q000097:blood / Q000493:pharmacokinetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D009288:Naproxen; D005480:Flurbiprofen; D007660:Ketoprofen; D014046:Tolmetin; D005279:Fenoprofen