TY - JOUR
T1 - Pharmacokinetics of the sequential metabolites of loteprednol etabonate in rats
AU - Wu, Whei Mei
AU - Huang, Fenglei
AU - Lee, Yangsuk
AU - Buchwald, Peter
AU - Bodor, Nicholas
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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.
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U2 - 10.1211/jpp.60.3.0003
DO - 10.1211/jpp.60.3.0003
M3 - Article
C2 - 18284808
AN - SCOPUS:39449133154
VL - 60
SP - 291
EP - 297
JO - Journal of Pharmacy and Pharmacology
JF - Journal of Pharmacy and Pharmacology
SN - 0022-3573
IS - 3
ER -