Identification of budesonide and prednisone as substrates of the intestinal drug efflux pump P-glycoprotein.
Steroid resistance is a major problem in the management of patients with inflammatory bowel disease. In Crohn disease, poor response to corticosteroids has been related to increased expression of the drug efflux pump, P-glycoprotein. However, it has not been investigated thoroughly whether corticosteroids commonly used for drug therapy in inflammatory bowel disease are substrates of P-glycoprotein. We tested the hypothesis that budesonide and prednisone are substrates of P-glycoprotein thereby possibly contributing to variable therapeutic effects. Polarized, basal to apical transport of [3H]budesonide and [3H]prednisone was studied in monolayers of L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1 cDNA) and Caco-2 cells, both of which express P-glycoprotein in their apical membrane. Drug transport was measured during 4 hours at substrate concentrations of 5 microM. Net transport rates and permeability coefficients were calculated. Inhibition of P-glycoprotein-mediated transport across Caco-2 monolayers was determined after addition of the P-glycoprotein inhibitor PSC-833. The net transport rate from the basolateral to the apical side was significantly higher in L-MDR1 than in LLC-PK1 cells for both budesonide and prednisone. Apparent permeability coefficients of budesonide and prednisone reflected polarized transport from basal to apical. PSC-833 inhibited the polarized transport of both corticosteroids. In conclusion, budesonide and prednisone were identified as substrates of the intestinal drug efflux pump, P-glycoprotein. Therefore, drug secretion via P-glyco-protein into gut lumen might play a more important role in pharmacokinetics and pharmacodynamics of these corticosteroids than currently appreciated in gastroenterological practice.
Dr. Falk Pharma GmbH, Freiburg, Germany. dilger@drfalkpharma.de
Karin
K
Dilger
Matthias
M
Schwab
Martin F
MF
Fromm
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019819:Budesonide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018929:Cell Culture Techniques; D003110:Colonic Neoplasms / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy*; D018432:Drug Resistance, Multiple; D006801:Humans; D010539:Permeability; D011241:Prednisone / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000893:Anti-Inflammatory Agents; D019819:Budesonide; D011241:Prednisone