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 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.
Footnotes
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This work was supported in part by a Grant-in-Aid for Scientific Research and a Grant-in-Aid for Scientific Research on Priority Areas of Biomolecular Design for Biotargeting (No. 296) from the Ministry of Education, Science, Sports and Culture of Japan.
- Abbreviations:
- CL
- total body clearance
- V1
- central volume of distribution
- Q
- intercompartmental clearance
- Vss
- volume of distribution at steady-state
- F
- bioavailability
- AUC
- area under the plasma concentration-time curve
- Tmax
- time to peak plasma concentration
- Cmax
- peak plasma concentration
- MRP
- multidrug resistance-associated protein
- Received September 12, 2001.
- Accepted December 2, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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