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), Δ1‐cortienic acid etabonate (AE) and Δ1‐cortienic acid (A), have been investigated in rats. Pharmacokinetic studies (two‐compartment model, 10 mg kg−1 intravenous bolus of AE or A) found the elimination of both AE (t1/2(β), 12.46 ± 1.18 min; CLtotal, 101.94 ± 5.80 mL min−1 kg−1; and Kel, 0.24 ± 0.02 min−1) and A (t1/2(β), 14.62 ± 0.46 min; CLtotal, 53.80 ± 1.40 mL min−1 kg−1; and Kel, 0.18 ± 0.02 min−1) to be significantly faster than that previously determined for the parent LE (t1/2(β), 43.41 ± 7.58 min; CLtotal, 67.40 ± 11.60 mL min−1 kg−1; and Kel, 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.