PERCUTANEOUS-ABSORPTION OF VANILLOIDS - IN-VIVO AND IN-VITRO STUDIES

The percutaneous absorption of three highly lipophilic analogs of caps aicin-vanillylnonanamide (VN), olvanil, and NE-21610-was measured in v ivo in the CD:VAF rat, and in vitro through excised CD:VAF and SkH:Fz rat skin and human cadaver skin. Absorption and skin metabolism were m onitored by radiolabel techniques. The rank order of penetration in al l species was VN > olvanil > NE-21610, in accordance with that expecte d from their physical properties, Rat skin was more permeable than hum an skin by factors ranging from 4 to 8 for VN, 10 to 20 for olvanil, a nd approximate to 10 to 100 for NE-21610. All three compounds were ext ensively metabolized during passage through fresh SkH:Fz rat skin, wit h the primary route of degradation for at least two of the compounds i nvolving hydrolysis of the amide bond (the metabolites of NE-21610 wer e not identified). For the in vitro studies a range of receptor soluti ons was employed to determine a set of conditions that best mimicked i n vivo absorption. The results with phosphate-buffered saline containi ng a preservative and 1-6% polyoxyethylene-20 oleyl ether (Oleth-20) w ere in good agreement with in vivo results for all three compounds for periods up to 24 h post-dose; after this time, in who absorption rate s declined but in vitro rates remained relatively constant. Buffered s aline or saline containing 0.5% bovine serum albumin led to marked und erestimates of in vivo penetration for olvanil and NE-21610, whereas a 1:1 ethanol: water solution led to gross overestimates of the in viva absorption rates for all three compounds.