Abstract
Effects of cytochrome P-450 3A- and P-glycoprotein (P-gp)-related compounds, erythromycin, midazolam, ketoconazole, verapamil, and quinidine, on transport of rhodamine 123 (Rho-123), a P-gp substrate, were studied in rat intestine and in Caco-2 cells. Ileum was mainly used in rat studies because this segment showed greater P-gp-mediated Rho-123 transport. In an in vitro everted rat ileum, all the compounds examined significantly inhibited the transport of Rho-123 from serosal to mucosal surfaces across the intestine, with different inhibitory potencies among these compounds. In an in vivo rat study, the exsorption of Rho-123 from blood to the intestinal lumen, which was evaluated as exsorption clearance of Rho-123 under a steady-state plasma concentration of Rho-123, was also inhibited when these compounds were added to the intestinal lumen. Similarly, transepithelial transport of Rho-123 from the basolateral to apical side across Caco-2 cell monolayers was inhibited by these compounds. A linear relationship was observed in their inhibitory potencies on Rho-123 transport between in vitro and in vivo studies using rat ileum and between studies with rat ileum and Caco-2 cells. P-gp-mediated transport across the intestine was found to be inhibited not only by P-gp-related but also by all the cytochrome P-450 3A-related compounds examined. Within experimental error, the relative inhibitory potencies were the same between the studies with rat ileum (in vivo, in vitro) and those with Caco-2 cells. Thus, it is suggested that the function of P-gp and its sensitivity to these drugs may be similar in rat intestine and Caco-2 cells.
Footnotes
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Send reprint requests to: Mikihisa Takano, Ph.D., Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. E-mail:takanom{at}pharm.hiroshima-u.ac.jp
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↵1 This work was supported in part by a grant-in-aid from the Tokyo Biochemical Research Foundation.
- Abbreviations:
- CYP
- cytochrome P-450
- P-gp
- P-glycoprotein
- Rho-123
- rhodamine 123
- TEER
- transepithelial electric resistance
- D-PBS
- Dulbecco’s PBS
- CLtotal
- total plasma clearance
- CLexp
- exsorption clearance
- CLurine
- urinary excretion clearance
- CLbile
- biliary excretion clearance
- Received July 22, 1998.
- Accepted November 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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