Development of a XXXX microdialysis model for determining synovial fluid pharmacokinetics of anti-arthritis compounds exemplified by @entity1499 .

@entity235 @entity1499 @entity1500 @entity130
PURPOSE: The purpose of this study was to develop and validate an animal model of drug disposition in synovial fluid (SF) by comparing microdialysis with arthrocentesis using the anti-arthritic drug @entity1499 ( @entity1500 ). METHODS: Microdialysis probes were calibrated in vitro with the no net flux method using @entity235 synovial fluid. The probes were implanted surgically into the stifle joint space of four @entity235 and were dialyzed overnight using a portable microinfusion pump. The membrane integrity of the probes was monitored by retrodialysis using an internal standard. After an intravenous bolus of 2.5 mg/kg of @entity1500 , unbound concentrations in synovial fluid, as well as total plasma concentrations, were measured by liquid chromatography tandam mass spectrometer (LC/MS/MS) in samples collected from 0 to 48 h postdose. RESULTS: The probe membrane remained intact at least 48 h after implantation. The mean probe recovery and unbound fraction of @entity1500 in SF were 46.8% and 44.8%, respectively. The unbound fraction of @entity1500 was 44% in synovial fluid. @entity1500 penetrated into the joint space rapidly, with maximal concentrations of 6.6 microM reached at approximately 1 h postdose. The unbound @entity1500 area under the curve in SF was approximately 40% of the total area under the curve in plasma. These data agree well with the previous data obtained for @entity1500 using arthrocentesis. CONCLUSION: In contrast with arthrocentesis, microdialysis enables the collection of multiple serial SF samples from individual animals with minimal @entity130 and potential blood contamination. This animal model should prove valuable for studying the disposition of new antiarthritis compounds or biomarkers in SF.
