Experimental evidence for amide hydrolysis of indomethacin in rabbit skin

Amide hydrolysis of indomethacin was investigated in rabbit skin using the isolated perfused rabbit ear model. Indomethacin was applied topically on the surface area of 4 rabbit ears using a 1% alcoholic solution (Elmetacin). Indomethacin and its hydrolytic product N-deschloro-benzoyl-indomethacin (DBI) were determined in the venous efflux. The concentrations of indomethacin and DBI increased during the first 160 min and remained constant thereafter, the concentrations amounting from 0.041 +/- 0.001 to 0.497 +/- 0.018 nmol/min/cm2 (indomethacin) and from 0.84 +/- 0.03 to 3.24 +/- 0.31 pmol/min/cm2 (DBI). Thus steady state was reached with both substances, indicating a formation of DBI in the range of 0.65-2.01%. Considering the low hydrolytic turnover rate, the limited efficacy of topically applied indomethacin in the treatment of skin diseases does not seem to be due to extensive metabolic inactivation via amide hydrolysis in this target organ.