Pharmacokinetics and Δ1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats

W. M. Wu, Y. Tang, Peter Buchwald, Nicholas Bodor

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 Δ1- cortienic acid (Δ1-CA), (ii) to investigate the excretion of Δ1-CA after PRN and LE administration, and (iii) to investigate the effect of Δ1-unsaturation on the excretion of Δ1-CA versus CA. Following a 10 mg·kg-1 intravenous bolus dose, the total clearance (CLtot) of PRN (27.0±1.4mL·min-1 kg-1) was significantly lower than that of LE (67.4±11.6mL·min-1 kg -1) or Δ1-CA (53.8±1.4mL·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 Δ1-CA (unchanged). The volume of distribution (Vdss) of PRN (823±78mL·kg-1) was significantly lower than that of LE (3078±79mL·kg -1) indicating that LE is more distributed to lipophilic tissues. Excretion studies have confirmed that Δ1-CA is indeed a metabolite of PRN. After intravenous injection of 10mg·kg-1, less than 1% of the administered PRN was excreted as Δ1-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 Δ1-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 Δ1 double bond (Δ1-unsaturation) does not affect significantly this metabolic conversion.

Original languageEnglish
Pages (from-to)412-416
Number of pages5
JournalPharmazie
Volume65
Issue number6
DOIs
StatePublished - Jun 1 2010

Fingerprint

Prednisolone
Intravenous Administration
Pharmacokinetics
Bile
Urine
Loteprednol Etabonate
cortienic acid
Intravenous Injections
Hydrocortisone
Adrenal Cortex Hormones
Hydrolysis
Liver

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Pharmacokinetics and Δ1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats. / Wu, W. M.; Tang, Y.; Buchwald, Peter; Bodor, Nicholas.

In: Pharmazie, Vol. 65, No. 6, 01.06.2010, p. 412-416.

Research output: Contribution to journalArticle

@article{c763708c789b4b26b4dddba2b1c52dfc,
title = "Pharmacokinetics and Δ1-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 Δ1- cortienic acid (Δ1-CA), (ii) to investigate the excretion of Δ1-CA after PRN and LE administration, and (iii) to investigate the effect of Δ1-unsaturation on the excretion of Δ1-CA versus CA. Following a 10 mg·kg-1 intravenous bolus dose, the total clearance (CLtot) of PRN (27.0±1.4mL·min-1 kg-1) was significantly lower than that of LE (67.4±11.6mL·min-1 kg -1) or Δ1-CA (53.8±1.4mL·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 Δ1-CA (unchanged). The volume of distribution (Vdss) of PRN (823±78mL·kg-1) was significantly lower than that of LE (3078±79mL·kg -1) indicating that LE is more distributed to lipophilic tissues. Excretion studies have confirmed that Δ1-CA is indeed a metabolite of PRN. After intravenous injection of 10mg·kg-1, less than 1{\%} of the administered PRN was excreted as Δ1-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 Δ1-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 Δ1 double bond (Δ1-unsaturation) does not affect significantly this metabolic conversion.",
author = "Wu, {W. M.} and Y. Tang and Peter Buchwald and Nicholas Bodor",
year = "2010",
month = "6",
day = "1",
doi = "10.1691/ph.2010.0524R",
language = "English",
volume = "65",
pages = "412--416",
journal = "Die Pharmazie",
issn = "0031-7144",
publisher = "Govi-Verlag Pharmazeutischer Verlag GmbH",
number = "6",

}

TY - JOUR

T1 - Pharmacokinetics and Δ1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats

AU - Wu, W. M.

AU - Tang, Y.

AU - Buchwald, Peter

AU - Bodor, Nicholas

PY - 2010/6/1

Y1 - 2010/6/1

N2 - 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 Δ1- cortienic acid (Δ1-CA), (ii) to investigate the excretion of Δ1-CA after PRN and LE administration, and (iii) to investigate the effect of Δ1-unsaturation on the excretion of Δ1-CA versus CA. Following a 10 mg·kg-1 intravenous bolus dose, the total clearance (CLtot) of PRN (27.0±1.4mL·min-1 kg-1) was significantly lower than that of LE (67.4±11.6mL·min-1 kg -1) or Δ1-CA (53.8±1.4mL·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 Δ1-CA (unchanged). The volume of distribution (Vdss) of PRN (823±78mL·kg-1) was significantly lower than that of LE (3078±79mL·kg -1) indicating that LE is more distributed to lipophilic tissues. Excretion studies have confirmed that Δ1-CA is indeed a metabolite of PRN. After intravenous injection of 10mg·kg-1, less than 1% of the administered PRN was excreted as Δ1-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 Δ1-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 Δ1 double bond (Δ1-unsaturation) does not affect significantly this metabolic conversion.

AB - 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 Δ1- cortienic acid (Δ1-CA), (ii) to investigate the excretion of Δ1-CA after PRN and LE administration, and (iii) to investigate the effect of Δ1-unsaturation on the excretion of Δ1-CA versus CA. Following a 10 mg·kg-1 intravenous bolus dose, the total clearance (CLtot) of PRN (27.0±1.4mL·min-1 kg-1) was significantly lower than that of LE (67.4±11.6mL·min-1 kg -1) or Δ1-CA (53.8±1.4mL·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 Δ1-CA (unchanged). The volume of distribution (Vdss) of PRN (823±78mL·kg-1) was significantly lower than that of LE (3078±79mL·kg -1) indicating that LE is more distributed to lipophilic tissues. Excretion studies have confirmed that Δ1-CA is indeed a metabolite of PRN. After intravenous injection of 10mg·kg-1, less than 1% of the administered PRN was excreted as Δ1-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 Δ1-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 Δ1 double bond (Δ1-unsaturation) does not affect significantly this metabolic conversion.

UR - http://www.scopus.com/inward/record.url?scp=77955296336&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955296336&partnerID=8YFLogxK

U2 - 10.1691/ph.2010.0524R

DO - 10.1691/ph.2010.0524R

M3 - Article

VL - 65

SP - 412

EP - 416

JO - Die Pharmazie

JF - Die Pharmazie

SN - 0031-7144

IS - 6

ER -