TRANSSYNOVIAL KINETICS OF IONAZOLAC AND ITS HYDROXY METABOLITE IN SYNOVITIS PATIENTS

Objective: The study was designed to characterize the synovial distrib ution profiles and kinetics of the non-steroidal antiinflammatory agen t, lonazolac, in patients with synovitis after multiple dosing with 30 0 mg tablets of lonazolac calcium salt. Methods: Forty patients (36 ma le, 4 female) aged 21 to 50 years (mean: 38 +/- 9 years) undergoing ar throscopy of the knee joint for surgical reasons were given 7 total do ses of drug administered as 300 mg oral tablets of lonazolac-calcium t aken twice daily. Patients were assigned to one of 4 treatment groups (n = 10) in which arthroscopy was carried out 1, 2, 6, or 12 h after t he seventh lonazolac dose. Samples of blood, synovial fluid, and synov ial membrane were obtained during each operation and used to determine total concentrations of lonazolac and its main metabolite in plasma a nd synovial fluid by HPLC assay with UV detection. Free lonazolac conc entrations in body fluids were determined after ultrafiltration by the same HPLC technique using a fluorescence detector. Tissue concentrati ons were assayed after additional steps using solvent and solid phase extractions. Total protein contents in plasma and synovial fluid were measured spectrophotometrically. Results: Plasma drug levels were high est at 1 hour after dosing with mean peak concentrations of 1.8 mg/l t otal lonazolac, 1.2 mg/l total metabolite, and 9 mu g/l free lonazolac . Profiles indicated a biphasic decline. Concentration vs. time profil es in synovial fluid were flattened compared to plasma profiles with m ean peak values of 440 mu g/l total lonazolac, 370 mu g/l total metabo lite, and 7 mu g/l free lonazolac attained 2 hours after dosing. The m ean unbound fraction of lonazolac was higher in synovial fluid (1.9%) compared to plasma (0.7%). Transsynovial partition coefficients increa sed continuously during a dosing interval from 0.16 to 3.15 for total lonazolac and from 0.56 to 5.05 for free lonazolac. Mean total protein contents for each group of patients ranged from 70 to 76 gn for plasm a and 32 to 42 g/l for synovial fluid. Total drug concentrations in sy novial membrane were highest in tissues obtained 1 hour after dosing w ith mean values of approximately 1.0 mu g/g dry weight. Tissue samples obtained at later times indicated that lonazolac profiles in tissue m ore closely resemble profiles obtained for plasma than for synovial fl uid. Protein concentration ratios (synovial fluid : plasma) were betwe en 0.45 and 0.58. Except for the absorption phase, transsynovial drug partition coefficients were always higher than the protein concentrati on ratios. Conclusions: Protein content is not an important factor for drug partition into inflamed joints after multiple dosing with lonazo lac. Lonazolac distributes well into synovial fluid with therapeutical ly effective concentrations of unbound drug measured within 2 hours af ter dosing. Total lonazolac levels in synovial fluid exceed those meas ured in plasma at 6 to 12 hours after administration.