Transsynovial distribution of ibuprofen in arthritic patients.

Free and total ibuprofen levels in serum and synovial fluid (SF) were determined in one male and 14 female arthritic patients (mean age 56 yr, range 19 to 77) after 400 mg three times daily for 2 days. Free drug was separated by ultrafiltration and assayed by a new highly sensitive and precise gas chromatographic-mass spectrometric technique. Total protein and albumin were assayed by automatic analyzer, and the routine serum biochemical profile obtained. Serum and SF nonesterified fatty acids (NEFAs) were methylated and assayed by gas chromatography. While both total protein and albumin levels were lower (P less than 0.01) in SF, NEFA levels did not differ (p greater than 0.05). Ibuprofen readily partitions into and binds strongly to joint fluid, the total level being about half that in serum. The ratio of total ibuprofen in SF to that in serum (x = 0.41 +/- 0.17) correlated with the albumin concentration ratio (r = 0.886) indicating that albumin binding is an important determinant of ibuprofen transsynovial distribution. A low total ibuprofen SF/serum ratio, apparent for three patients on concomitant aspirin therapy, is consistent with reports of an ibuprofen-salicylate interaction. Free ibuprofen in SF (0.192 +/- 0.086 microgram ml-1) did not differ (p greater than 0.05) from serum free levels (x = 0.251 +/- 0.139 microgram ml-1), supporting the concept of the synovial cavity as a compartment readily accessible to unbound drug species. Multiple regression analyses revealed relative independence of free concentration on total levels, and the small positive and negative influences of NEFAs and albumin concentrations. Bilirubin, uric acid, cholesterol, triglycerides, and chloride ion did not correlate with serum free concentration.

Ultrafiltration in serum protein binding determinations.

the ultrafiltration technique was evaluated theoretically and experimentally for use in clinical serum binding determinations. It is apparent from free energy considerations that the ultrafiltrate concentration approaches the true free concentration only as the pressure gradient causing flow reduces to zero. The theory presented accounts for the previously unexplained lower ultrafiltrate concentration observed at higher filtration pressures. Mathematical simulations of the molecular separation show that the ultrafiltrate concentration remains constant during filtration, and, thus, binding equilibria are not disturbed by this procedure, suggesting that an arbitrary restriction on the volume filtered is unnecessary. This finding greatly extends the value of the ultrafiltration technique in clinical binding determinations, especially for strongly bound, potent drugs where assays may be insufficiently sensitive to detect the extremely small free fraction reliably. These theoretical findings were verified experimentally by ultrafiltration of salicylate, ibuprofen, and carprofen in buffer, purified proteins, and whole serum.