title: The role of inter-segmental differences in P-glycoprotein expression and activity along the rat small intestine in causing the double-peak phenomenon of substrate plasma concentration.
abstract: 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 reached its 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.
authors: Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan.
authors: Sho
authors: S
authors: Wada
authors: Takashi
authors: T
authors: Kano
authors: Suzune
authors: S
authors: Mita
authors: Yoko
authors: Y
authors: Idota
authors: Kaori
authors: K
authors: Morimoto
authors: Fumiyoshi
authors: F
authors: Yamashita
authors: Takuo
authors: T
authors: Ogihara
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D004386:Duodenum / Q000378:metabolism; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D051381:Rats; D020112:Rhodamine 123 / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020112:Rhodamine 123