REGIONAL DRUG-DELIVERY .2. RELATIONSHIP BETWEEN DRUG TARGETING INDEX AND PHARMACOKINETIC PARAMETERS FOR 3 NONSTEROIDAL ANTIINFLAMMATORY DRUGS USING THE RAT AIR POUCH MODEL OF INFLAMMATION

Purpose. To quantify the advantage gained by direct administration to a target site for two non-steroidal anti-inflammatory drugs (NSAIDs) p iroxicam and diclofenac in the rat air pouch model of inflammation. To derive a model relating drug targeting index (DTI) to the pharmacokin etic parameters of the target and systemic sites, and to compare predi ctions with observations. Methods. DTI was calculated based on area un der the concentration time curve at target (pouch) and systemic site ( venous blood) following administration into and sampling from both sit es. A model was derived relating DTI to systemic clearance, target per meability, plasma protein binding and fraction of the targeted dose th at is systemically available. Results, Both NSAIDs exhibited linear ph armacokinetics over the dose ranges studies. They differed primarily i n total body clearance which was approximately 16 fold greater for dic lofenac (213 mi hr-' per 250 g) than piroxicam (13 ml hr(-1) per 250 g ). Observed DTIs (11, 114 and 276 for piroxicam, S[+]ibuprofen [studie d previously] and diclofenac) were ranked in order of total body clear ance but were approximately 7.5 fold lower than predicted (101, 700 an d 2214 respectively). Conclusions. The discrepancy was explained by th e influx of the plasma binding protein, albumin, into the target site due to increased vascular permeability associated with the inflammator y response. The originally derived equation for DTI, which assumed onl y unbound drug diffuses across the target site, was modified to take i nto account the simultaneous flux of bound drug.