Samir_2018_Xenobiotica__1

1. Loteprednol etabonate (LE) is a soft corticosteroid with two labile ester bonds at 17alpha- and 17beta-positions. Its corticosteroidal activity disappears upon hydrolysis of either ester bond. Hydrolysis of both ester bonds produces the inactive metabolite, Delta(1)-cortienic acid (Delta(1)-CA). 2. The simple high performance liquid chromatography method using acetic acid gradient was developed for the simultaneous determination of LE and its acidic metabolites. 3. LE was hydrolyzed in rat plasma with a half-life of 9 minutes. However, LE hydrolysis was undetectable in rat liver and intestine. LE hydrolysis in rat plasma was completely inhibited by paraoxon and bis (p-nitrophenyl) phosphate, thus identifying carboxylesterase as the LE hydrolase. Rat plasma carboxylesterase had a Km of 6.7 muM for LE. 4. In contrast to the disappearance rate of LE in rat plasma, the formation rate of 17alpha-monoester and Delta(1)-CA was markedly low, and a main hydrolysate of LE was not detected in rat plasma. 5. The metabolism of LE proceeded via different pathways in human and rat plasma. LE was slowly hydrolyzed by paraoxonase in human plasma to 17alpha-monoester with a half-life of 12 hours, but by carboxylesterase in rat plasma to yield undetectable products, presumed to include the unstable 17beta-monoester.