Skin disposition of drugs after topical application in hairless rats

Drug fraction transported from a topical formulation on skin to subcutaneou s tissues or muscles is dependent on the physicochemical properties of the entrapped drug. Cutaneous disposition of model drugs, antipyrine (ANP), lid ocaine (LC) and piroxicam (PXC) as well as flurbiprofen (FP) was thus evalu ated in hairless rats in which an agar gel disc was subcutaneously inserted into the abdominal region as a drug receptor and a drug donor cell was pla ced above it. Time courses of plasma level and agar gel amount were measure d after topical application of 50% ANP, 3% LC, 1% PXC and 1% FP in hydroxyp ropylcellulose gel. Percutaneous absorption clearance of unionized form, CL ab* was proportional to true octanol/water distribution coefficient and the order of FP>PXC>LC>ANP, suggesting that skin permeation of the drug was de termined mainly by its distribution from the formulation to the skin barrie r. PXC, however, had a relatively low flux compared to the other three drug s, probably due to its high molecular weight and melting point. Migration c learance of unionized form from systemic circulation to the subcutaneous ag ar gel, CLg* was also influenced by the lipophilicity of drugs. On the othe r hand, fraction from the formulation to the systemic circulation was in th e order of PXC>FP>ANP>LC. This fraction was much higher than the direct mig ration fraction from the formulation to the subcutaneous agar gel. Factors determining for these fractions are still unclear. A drug having a low lipo philicity and a low protein binding, however, had a tendency to have a grea t targeting ability to the subcutaneous agar gel. In addition, most of the drug in the agar gel was contributed by the direct Bow from formulation, no t from the systemic circulation. The present in situ experimental method is a useful tool to evaluate skin disposition of drugs. Detailed understandin g of the skin disposition of drugs from several formulations will enable th e finding of a good drug and formulation candidates.