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
Aj. Stevens et al., 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, Pharmaceutical research, 12(12), 1995, pp. 1987-1996
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.