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; CL_total, 101.94 ± 5.80 mL min^-1 kg ^-1; and K_el, 0.24 ± 0.02 min^-1) and A (t1/2_(β), 14.62 ± 0.46 min; CL_total, 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_(β), 43.41 ± 7.58 min; CL_total, 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.