Pharmacokinetic role of P-glycoprotein in oral bioavailability and intestinal secretion of grepafloxacin in vivo

Hiroaki Yamaguchi, Ikuko Yano, Hideyuki Saito, Ken Ichi Inui

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of grepafloxacin and levofloxacin in vivo. Plasma concentrations of grepafloxacin and levofloxacin after intravenous and intraintestinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of grepafloxacin were significantly decreased to 60 and 63% of the corresponding control values by cyclosporin A. The apparent oral clearance of grepafloxacin was decreased to 33% of the control, and the bioavailability of grepafloxacin was increased to 95% by cyclosporin A from 53% in the controls. Intestinal clearance of grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance of grepafloxacin was also decreased to one-third with cyclosporin A in rats. Intestinal secretion of grepafloxacin in mdr1a/1b (-/-) mice, which lack mdr1-type P-glycoproteins, was significantly decreased compared with wild-type mice, although the biliary secretion was similar. Intestinal secretion of grepafloxacin in wild-type mice treated with cyclosporin A was comparable to those in mdr1a/1b (-/-) mice with or without cyclosporin A, indicating that cyclosporin A completely inhibited P-glycoprotein-mediated intestinal transport of grepafloxacin. In conclusion, our results indicated that mediated the intestinal secretion of grepafloxacin and limited the bioavailability of this drug in vivo.

Original languageEnglish
Pages (from-to)1063-1069
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume300
Issue number3
DOIs
Publication statusPublished - 2002 Mar 4

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Pharmacokinetic role of P-glycoprotein in oral bioavailability and intestinal secretion of grepafloxacin in vivo'. Together they form a unique fingerprint.

  • Cite this