Effect of carrageenan-induced acute peripheral inflammation on the pharmacokinetics and hepatic metabolism of midazolam in rats

Noriko Kajikawa, Masami Doi, Jun Ichi Kusaba, Tetsuya Aiba

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The effect of carrageenan-induced acute peripheral inflammation (API) on the pharmacokinetics of the hepatically metabolizing compound midazolam (MDZ) was investigated in rats. Rats were subcutaneously treated with λ-carrageenan in the hind paw to induce API. When MDZ was intravenously administered in male rats, it was demonstrated that the plasma concentration profile of MDZ slightly alters in API rats compared with that in normal rats, while the plasma concentrations of its metabolites, 4-hydroxy and 1′-hydroxy MDZ, are markedly reduced with delayed appearances in API rats. In the incubation study with rat liver microsomes, it was clearly indicated that the generation rates of the two metabolites decrease in API rats. Western blot analysis revealed that hepatic CYP3A1 expression increases, while CYP3A2 expression decreases in API rats. In female rats, in which CYP3A2 is barely expressed in the liver, MDZ metabolism is little affected by API. These findings indicate that the hepatic handling of a therapeutic compound varies with API, largely due to altered hepatic expression of the drug-metabolizing enzyme.

Original languageEnglish
Pages (from-to)400-406
Number of pages7
JournalDrug Metabolism And Pharmacokinetics
Volume29
Issue number5
DOIs
Publication statusPublished - 2014

Keywords

  • Acute inflammation
  • CYP3A2
  • Carrageenan
  • Hepatic metabolism
  • Midazolam
  • Sex difference

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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