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Regional difference in P-glycoprotein function in rat intestine.
Drug Metab Pharmacokinet. 2005 Apr; 20(2):100-6.DM

Abstract

It has been reported that inhibition of the P-glycoprotein (P-gp) results in the improved absorption of P-gp substrate in the intestinal tract. In fact, the increased permeability of P-gp substrate across the intestinal epithelium was observed following inhibition of P-gp in in vitro experiments. To develop the formulation containing P-gp inhibitor and P-gp substrate for practical use, it is necessary to know whether the results obtained in the in vitro experiments are reproducible at whole body level. It is also important to find out the regional difference of the P-gp activity in the intestinal tract. In this study, we examined whether verapamil, a specific inhibitor of P-gp, improves the absorption of rhodamine123 (Rho123), a substrate of P-gp, from the jejunum, ileum, and colon of rats using the in situ loop method. The water content in the loop decreased during the experiment, resulting in a significant change of the Rho123 concentration in the loop. Thus, to accurately determine the absorption rate of Rho123, it was necessary to measure the water movement. It was found that there was a regional difference in the water movement, i.e., greatest in colon, followed by ileum. Verapamil did not change the water movement in any intestinal regions. When the concentration of Rho123 in the loop was corrected by water movement, the Rho123 clearance was in the order of ileum (1.15 microL/min/cm), colon (0.83 microL/min/cm) and jejunum (0.47 microL/min/cm). In the presence of verapamil, the Rho123 clearance was significantly increased at jejunum and ileum but not in colon (ileum: 2.08 microL/min/cm, colon: 1.14 microL/min/cm, jejunum: 1.28 microL/min/cm). These results suggest that P-gp inhibits the drug absorption in jejunum and ileum. From these results, it is possible to evaluate the role of P-gp and its regional difference in the in situ experiments. In particular, the inhibition of P-gp results in an increase in absorption of the P-gp substrate limited to jejunum and ileum.

Authors+Show Affiliations

Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. iida_aiko@allergan.comNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15855720

Citation

Iida, Aiko, et al. "Regional Difference in P-glycoprotein Function in Rat Intestine." Drug Metabolism and Pharmacokinetics, vol. 20, no. 2, 2005, pp. 100-6.
Iida A, Tomita M, Hayashi M. Regional difference in P-glycoprotein function in rat intestine. Drug Metab Pharmacokinet. 2005;20(2):100-6.
Iida, A., Tomita, M., & Hayashi, M. (2005). Regional difference in P-glycoprotein function in rat intestine. Drug Metabolism and Pharmacokinetics, 20(2), 100-6.
Iida A, Tomita M, Hayashi M. Regional Difference in P-glycoprotein Function in Rat Intestine. Drug Metab Pharmacokinet. 2005;20(2):100-6. PubMed PMID: 15855720.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regional difference in P-glycoprotein function in rat intestine. AU - Iida,Aiko, AU - Tomita,Mikio, AU - Hayashi,Masahiro, PY - 2005/4/28/pubmed PY - 2005/7/13/medline PY - 2005/4/28/entrez SP - 100 EP - 6 JF - Drug metabolism and pharmacokinetics JO - Drug Metab Pharmacokinet VL - 20 IS - 2 N2 - It has been reported that inhibition of the P-glycoprotein (P-gp) results in the improved absorption of P-gp substrate in the intestinal tract. In fact, the increased permeability of P-gp substrate across the intestinal epithelium was observed following inhibition of P-gp in in vitro experiments. To develop the formulation containing P-gp inhibitor and P-gp substrate for practical use, it is necessary to know whether the results obtained in the in vitro experiments are reproducible at whole body level. It is also important to find out the regional difference of the P-gp activity in the intestinal tract. In this study, we examined whether verapamil, a specific inhibitor of P-gp, improves the absorption of rhodamine123 (Rho123), a substrate of P-gp, from the jejunum, ileum, and colon of rats using the in situ loop method. The water content in the loop decreased during the experiment, resulting in a significant change of the Rho123 concentration in the loop. Thus, to accurately determine the absorption rate of Rho123, it was necessary to measure the water movement. It was found that there was a regional difference in the water movement, i.e., greatest in colon, followed by ileum. Verapamil did not change the water movement in any intestinal regions. When the concentration of Rho123 in the loop was corrected by water movement, the Rho123 clearance was in the order of ileum (1.15 microL/min/cm), colon (0.83 microL/min/cm) and jejunum (0.47 microL/min/cm). In the presence of verapamil, the Rho123 clearance was significantly increased at jejunum and ileum but not in colon (ileum: 2.08 microL/min/cm, colon: 1.14 microL/min/cm, jejunum: 1.28 microL/min/cm). These results suggest that P-gp inhibits the drug absorption in jejunum and ileum. From these results, it is possible to evaluate the role of P-gp and its regional difference in the in situ experiments. In particular, the inhibition of P-gp results in an increase in absorption of the P-gp substrate limited to jejunum and ileum. SN - 1347-4367 UR - https://www.unboundmedicine.com/medline/citation/15855720/Regional_difference_in_P_glycoprotein_function_in_rat_intestine_ L2 - http://joi.jlc.jst.go.jp/JST.JSTAGE/dmpk/20.100?from=PubMed DB - PRIME DP - Unbound Medicine ER -