Analysis of skin disposition of flurbiprofen after topical application in hairless rats

Cutaneous disposition of topically applied flurbiprofen (FP) was evaluated using a new in situ experimental model in hairless rats. A disk-shaped agar gel (3.85 cm in diameter and 0.5 cm in thickness) was subcutaneously impla nted in the abdominal region of rats as a drug receptor, and a drug donor c ell was subsequently placed above this agar gel. No significant pharmacokin etic modification of FP was observed as a result of this experimental proce dure. A bolus injection and a constant intravenous infusion of FP were appl ied to the rats, followed by an analysis of FP levels in the plasma and aga r gels. Using these results, the clearance rate of FP from the systemic cir culation to the gel could be calculated. FP (1% gel formulation, 1.0 g/3.14 cm(2)) was then topically applied to the skin of these rats. From these ex periments, the amount of FP that migrated from the formulation to the syste mic circulation and the amount of FP that migrated directly to the agar gel across the skin, over 10 h, were separately evaluated to be 235.4 and 2.0 mu g, respectively. Thus, most of the FP was absorbed into the systemic cir culation The effect of endogeneous vasoactive compounds and penetration enh ancers on the FP disposition within skin was also determined. Epinephrine a nd bradykinin were used as vasoactive compounds that were entrapped in agar gel, and an isopropyl myristate system (IPM system) and a l-menthol-ethano l-glycerin-water system (MEGW system) were used as enhancers in the formula tion. Epinephrine enhanced the direct delivery of FP into the agar gel to m ore than ten times its former level, in spite of the fact that it had no ef fect on systemic delivery. Bradykinin strengthened systemic delivery slight ly, without changing the quantity of FP in the gel. IPM increased only the systemic delivery of FP, as was the case with bradykinin, whereas the MEGW system markedly increased both the blood concentration and the quantity of FP in the gel (13 and 200 times, respectively). This technique has proven t o be an effective tool for the quantitative evaluation of cutaneous disposi tion of a topically applied drug. (C) 1999 Elsevier Science BN. All rights reserved.