PHARMACOKINETIC STUDIES OF METHOTREXATE IN PLASMA AND SYNOVIAL-FLUID FOLLOWING IV BOLUS AND TOPICAL ROUTES OF ADMINISTRATION IN DOGS

Purpose. The pharmacokinetic properties of methotrexate (MTX) in the p lasma and synovial fluid (SF) after bolus IV and topical administratio n were studied in dogs to assess the feasibility of topical delivery o f MTX for the treatment of rheumatoid arthritis. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and to pically applied on the elbow and stifle joints of dogs. SF was collect ed by inserting a needle with syringe into the joint space. Drug conce ntrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrat ions in SF occurrred at 38 +/- 5 min following bolus IV dose, indicati ng the presence of a substantial diffusion barrier between the plasma and SE The plasma/Sf concentration ratios of 1.16 +/- 0.25 were mainta ined after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 +/- 1.2 hr) and SF ( 12.7 +/- 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 +/- 0.21 hr) was longer than that in plasma (2.56 +/- 0.20 hr), probably due to the slow distribution of MTX to SE After top ical dose, MTX concentrations in plasma reached the steady state at si milar to 4 hr, lasting for similar to 20 hr. The bioavailability of MT X from the gel was 11.8 +/- 3.3% of the applied dose, but muscle tissu es beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical differenc e in SF concentrations of MTX between drug treated and untreated joint s 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.