title: Pharmacokinetics and delta1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats.
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.
authors.affiliation: Center for Drug Discovery College of Pharmacy, University of Florida, Gainesville 32610-0497, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.forename: P
authors.initials: P
authors.lastname: Buchwald
authors.forename: N
authors.initials: N
authors.lastname: Bodor
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007275:Injections, Intravenous; D000069559:Loteprednol Etabonate; D008297:Male; D011239:Prednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000730:Androstadienes; D000893:Anti-Inflammatory Agents; C527981:delta1-cortienic acid; D011239:Prednisolone; D000069559:Loteprednol Etabonate