Pharmacokinetic Role of P-Glycoprotein in Oral Bioavailability and Intestinal Secretion of Grepafloxacin in Vivo

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 Pglycoprotein 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 (Ϫ/Ϫ) 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 (Ϫ/Ϫ) 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.

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

“…pre-administration [34]. The ratio of intestinal secretion to dose of grepafloxacin in both types of mice was in the range of 5-7%.…”

Correlation between Apical Localization of Abcc2/Mrp2 and Phosphorylation Status of Ezrin in Rat Intestine

“…The distinct but sometimes overlapping substrate specificities of these efflux transporters have been shown previously (Chan et al, 2004). Indeed, a significant increase in the oral absorption of their substrates, including drugs and carcinogens, was confirmed in animals genetically deficient in these transporters (Dietrich et al, 2001;Yamaguchi et al, 2002).…”

“…The distinct but sometimes overlapping substrate specificities of these efflux transporters have been shown previously (Chan et al, 2004). Indeed, a significant increase in the oral absorption of their substrates, including drugs and carcinogens, was confirmed in animals genetically deficient in these transporters (Dietrich et al, 2001;Yamaguchi et al, 2002).Several reports indicated the disparity between mRNA and protein expression of Abcc2 in the intestine. Naud et al (2007) reported that Abcc2 protein expression was reduced to approximately 40% of that of the control during chronic renal failure in rats, but its mRNA expression was unaffected.…”

Altered Diurnal Rhythm of Intestinal Peptide Transporter by Fasting and Its Effects on the Pharmacokinetics of Ceftibuten

“…Rats were anesthetized with sodium pentobarbital (40 mg/kg). For intraintestinal infusion of CETB, a catheter with a 26-gauge needle was carefully fixed with cyanoacrylate glue into the middle part of the duodenum (Yamaguchi et al, 2002). For intravenous infusion of CETB, the jugular vein was cannulated with a polyethylene-10 tube (BD Biosciences, Parsippany, NJ).…”