title: Nonlinear absorption of methylprednisolone by absorptive and secretory transporters.
abstract: The intestinal absorption rate constant of methylprednisolone (MP) evaluated by the loop method increased significantly with increasingly higher concentrations of the drug up to 500 microM in a nonlinear fashion but did not increase further at higher concentrations. Mucosal-to-serosal directed permeation of MP across rat jejunal sheets also increased in a nonlinear fashion in a low concentration range (100-150 microM), followed by a decrease as the concentration increased further, whereas serosal-to-mucosal directed permeation decreased in a concentration-dependent manner. Vectorial transport of MP across Caco-2 cell monolayers was observed, with greater transport in the basolateral-to-apical direction at 37 degrees C. These observations suggest that MP is taken up in the intestinal epithelial cells by a carrier-mediated transport mechanism. The absorptive and secretory clearance of MP increased and decreased with P-glycoprotein (P-gp) inhibitors, respectively. These results strongly suggest that MP is secreted into the intestinal lumen predominantly by P-gp. We conclude that intestinal transport of MP involves P-gp or some other transporters in both the absorptive and secretory directions, and complex nonlinear intestinal absorption characteristics can be ascribed to the existence of multiple transport mechanisms.
authors.affiliation: Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. tomita@ps.toyaku.ac.jp
authors.forename: Mikio
authors.initials: M
authors.lastname: Tomita
authors.forename: Atsuko
authors.initials: A
authors.lastname: Watanabe
authors.forename: Ikue
authors.initials: I
authors.lastname: Fujinaga
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamakawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hayashi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D008775:Methylprednisolone