Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367

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Role of inter-segmental differences in P-glycoprotein expression and activity along rat small intestine in causing double-peak phenomena of substrate plasma concentration
Sho WadaTakashi KanoSuzune MitaYoko IdotaKaori MorimotoFumiyoshi YamashitaTakuo Ogihara
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論文ID: DMPK-12-RG-005

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  Conflicting results have been reported on segmental differences in expression of P-glycoprotein (P-gp) along the small intestine of animals and humans. In this study, we investigated P-gp mRNA and protein levels within each of nine segments of rat small intestine. In addition, P-gp activity in each segment was evaluated in terms of permeability of Rhodamine123 (Rho123), a typical P-gp substrate, using the serial intestinal non-everted sac method. The P-gp mRNA levels tended to increase from the duodenum to the ileum, with peaks in the upper and lower ileum, while P-gp protein level indicated maximum in the middle ileum. The activity of P-gp was also the highest in the middle ileum, and was highly correlated with P-gp protein level. The double-peaked plasma concentration profile that was observed following oral administration of Rho123 to rats could be well reproduced by an intestinal compartmental kinetic model incorporating inter-segmental differences of absorption and excretion rate constants. Our results suggest that the heterogeneous distribution of P-gp along the small intestine plays a key role in causing the double-peak of plasma concentration of P-gp substrates following oral administration to rats.
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© 2012 by The Japanese Society for the Study of Xenobiotics
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