Nonlinear absorption of methylprednisolone by absorptive and secretory transporters.
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.
Tomita
Mikio
M
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
Watanabe
Atsuko
A
Fujinaga
Ikue
I
Yamakawa
Tomoko
T
Hayashi
Masahiro
M
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D008775:Methylprednisolone