Pharmacokinetics and delta1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats.

W M Wu, Y Tang, P Buchwald, N Bodor

Index: Pharmazie 65(6) , 412-6, (2010)

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Abstract

Detailed pharmacokinetic (PK) studies in rats were performed (i)to compare the PK of prednisolone (PRN) and loteprednol etabonate (LE, a soft corticosteroid) as well as their common inactive metabolite delta1-cortienic acid (delta1-CA), (ii) to investigate the excretion of delta1-CA after PRN and LE administration, and (iii) to investigate the effect of delta1-unsaturation on the excretion of delta1-CA versus CA. Following a 10 mg x kg(-1) intravenous bolus dose, the total clearance (CL(tot)) of PRN (27.0 +/- 1.4 mL x min(-1) kg(-1)) was significantly lower than that of LE (67.4 +/- 11.6 mL x min(-1) kg(-1)) or delta1-CA (53.8 +/- 1.4 mL x min(-1) kg(-1)) indicating that the metabolism/elimination of PRN in the liver (primarily, conjugation) may be less efficient than that of LE (primarily, hydrolysis) or delta1-CA (unchanged). The volume of distribution (Vd(ss)) of PRN (823 +/- 78 mL x kg(-1)) was significantly lower than that of LE (3078 +/- 79 mL x kg(-1)) indicating that LE is more distributed to lipophilic tissues. Excretion studies have confirmed that delta1-CA is indeed a metabolite of PRN. After intravenous injection of 10 mg x kg(-1), less than 1% of the administered PRN was excreted as delta1-CA by 4 h (0.38 +/- 0.10% in bile and 0.18 +/- 0.04% in urine), significantly less than for LE (17.01 +/- 2.09% in bile and 2.53 +/- 1.17% in urine) indicating that extent of this metabolic transformation can indeed be affected by molecular design. At doses of 100 mg/kg, the proportion of delta1-CA excreted after PRN administration (0.12 +/- 0.03% in bile and 0.19 +/- 0.03% in urine) was similar to that of CA excreted after hydrocortisone administration (0.11 +/- 0.03% in bile and 0.22 +/- 0.04% in urine) indicating that the presence of the delta1 double bond (delta1-unsaturation) does not affect significantly this metabolic conversion.