Transsynovial kinetics of lonazolac and its hydroxy metabolite in synovitis patients.

摘要

OBJECTIVE: The study was designed to characterize the synovial distribution profiles and kinetics of the non-steroidal antiinflammatory agent, lonazolac, in patients with synovitis after multiple dosing with 300 mg tablets of lonazolac calcium salt. METHODS: Forty patients (36 male, 4 female) aged 21 to 50 years (mean: 38+/-9 years) undergoing arthroscopy of the knee joint for surgical reasons were given 7 total doses of drug administered as 300 mg oral tablets of lonazolac-calcium taken 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 the seventh lonazolac dose. Samples of blood, synovial fluid, and synovial membrane were obtained during each operation and used to determine total concentrations of lonazolac and its main metabolite in plasma and synovial fluid by HPLC assay with UV detection. Free lonazolac concentrations in body fluids were determined after ultrafiltration by the same HPLC technique using a fluorescence detector. Tissue concentrations 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 highest at 1 hour after dosing with mean peak concentrations of 1.8 mg/l total lonazolac, 1.2 mg/l total metabolite, and 9 microg/l free lonazolac. Profiles indicated a biphasic decline. Concentration vs. time profiles in synovial fluid were flattened compared to plasma profiles with mean peak values of 440 microg/l total lonazolac, 370 microg/l total metabolite, and 7 microg/l free lonazolac attained 2 hours after dosing. The mean unbound fraction of lonazolac was higher in synovial fluid (1.9%) compared to plasma (0.7%). Transsynovial partition coefficients increased 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 g/l for plasma and 32 to 42 g/l for synovial fluid. Total drug concentrations in synovial membrane were highest in tissues obtained 1 hour after dosing with mean values of approximately 1.0 microg/g dry weight. Tissue samples obtained at later times indicated that lonazolac profiles in tissue more closely resemble profiles obtained for plasma than for synovial fluid. Protein concentration ratios (synovial fluid : plasma) were between 0.45 and 0.58. Except for the absorption phase, transsynovial drug partition coefficients were always higher than the protein concentration ratios. CONCLUSIONS: Protein content is not an important factor for drug partition into inflamed joints after multiple dosing with lonazolac. Lonazolac distributes well into synovial fluid with therapeutically effective concentrations of unbound drug measured within 2 hours after dosing. Total lonazolac levels in synovial fluid exceed those measured in plasma at 6 to 12 hours after administration.