Correlation between physicochemical characteristics, pharmacokinetic properties and transdermal absorption of NSAID's

The plasma concentrations of indomethacin, ketoprofen and piroxicam were determined as a function of time after topical gel administration, using male ED IX rats. Physicochemical characteristics such as the lipid/water partition coefficient (log P value), molecular mass of the respective drugs, percentage unionized moiety and the solubility constraint of the drug in the stratum corneum were investigated and correlated with the AUC values obtained after transdermal absorption of these drugs. One gram gel samples (equivalent to 5 mg drug) were applied to the dorsal areas of the rats (n = 5). The rats were sacrificed at 2, 4, 8, 24, 30, 48 and 96 h after gel administration. Plasma concentrations of indomethacin, ketoprofen and piroxicam were determined using a high performance liquid chromatography (HPLC) method. Sample preparation involved protein precipitation and centrifugation. The log P values obtained from literature for piroxicam, ketoprofen and indomethacin, (3.08, 0.97 and 1.8, respectively) correlated with the area under the plasma-time curve (AUC) values determined 527.00 (piroxicam) 269.45 (ketoprofen) and 243.22 (indomethacin) mu g/ml/h, respectively. It was concluded that the most reliable parameter was the lipophilic character of a drug (log P value). The molecular mass, solubility constraint and percentage unionized moiety did not show any correlation concerning transdermal absorption and can therefore not be used on their own in the prediction thereof. However, all the parameters including the pharmacokinetic properties of drugs should be considered in combination in the prediction of possible transdermal drug delivery. (C) 1998 Elsevier Science B.V. All rights reserved.