PT  - JOURNAL ARTICLE
AU  - Hiroaki Yamaguchi
AU  - Ikuko Yano
AU  - Hideyuki Saito
AU  - Ken-ichi Inui
TI  - Pharmacokinetic Role of P-Glycoprotein in Oral Bioavailability and Intestinal Secretion of Grepafloxacin in Vivo
AID  - 10.1124/jpet.300.3.1063
DP  - 2002 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1063--1069
VI  - 300
IP  - 3
4099  - http://jpet.aspetjournals.org/content/300/3/1063.short
4100  - http://jpet.aspetjournals.org/content/300/3/1063.full
SO  - J Pharmacol Exp Ther2002 Mar 01; 300
AB  - 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 inmdr1a/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 P-glycoprotein mediated the intestinal secretion of grepafloxacin and limited the bioavailability of this drug in vivo. The American Society for Pharmacology and Experimental Therapeutics