Pharmacokinetics of the sequential metabolites of loteprednol etabonate in rats.

Pharmacokinetics, metabolism and excretion of two sequential inactive metabolites of the soft corticosteroid loteprednol etabonate (LE), Delta(1)-cortienic acid etabonate (AE) and Delta(1)-cortienic acid (A), have been investigated in rats. Pharmacolkinetic studies (two-compartment model, 10 mg kg(-1) intravenous bolus of AE or A) found the elimination of both AE (t1/2((beta)), 12.46 +/- 1.18 min; CLtotal, 101.94 +/- 5.80 mL min(-1) kg(-1); and K-el, 0.24 +/- 0.02 min(-1)) and A (t1/2((beta)), 14.62 +/- 0.46 min; CLtotal, 53.80 +/- 1.40 mL min(-1) kg(-1); and K-el, 0.18 +/- 0.02 min(-1)) to be significantly faster than that previously determined for the parent LE (t1/2((beta)), 43.41 +/- 7.58 min; CLtotal, 67.40 +/- 11.60 mL min(-1) kg(-1); and K-el 0.071 +/- 0.024 min(-1)). For metabolism and excretion evaluations, 1 and 10 mg kg(-1) of either AE or A were intravenously administered, and the urine and bile were collected. AE and A rapidly reached their peak concentrations in the bile and urine, and most of them were eliminated within one hour. Total cumulative excretions at 4 h after 1 and 10 mg kg(-1) injections were 85.51 +/- 3.38% and 67.50 +/- 2.67% for AE, and 71.90 +/- 3.72% and 37.73 +/- 2.69% for A in bile; and 4.84 +/- 1.87% and 13.85 +/- 3.27% for AE, and 24.28 +/- 8.44% and 22.35 +/- 1.12% for A in urine, respectively. After AE administration, the excretion of AE was > 90%, and A was < 10% in all cases, indicating that the elimination of AE was much faster than its metabolism (to A). In a manner similar to that seen for LE, dose-dependent elimination was observed both in AE and A. These results suggested that both AE and A were ideal leads for the design of soft steroids based on the inactive metabolite approach.