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P‐Glycoprotein‐170 inhibition significantly reduces cortisol and ciclosporin efflux from human intestinal epithelial cells and T lymphocytes
Author(s) -
Farrell R. J.,
Menconi M. J.,
Keates A. C.,
Kelly C. P.
Publication year - 2002
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1046/j.1365-2036.2002.01238.x
Subject(s) - ciclosporin , verapamil , p glycoprotein , efflux , vinblastine , intracellular , endocrinology , medicine , cell culture , biology , multiple drug resistance , chemotherapy , biochemistry , calcium , antibiotics , genetics
Aim: To assess the role of P‐glycoprotein‐170 (P‐gp) in transporting cortisol and ciclosporin from human intestinal epithelium and T lymphocytes. Methods: The effect of P‐gp inhibitors (verapamil, 0–100 μ M ; PSC 833, 0–20 μ M ) on the intracellular accumulation of 3 H‐cortisol and 3 H‐ciclosporin was studied in confluent layers of human Caco‐2 cells ( n =6), a P‐gp‐dependent absorptive intestinal epithelial cell phenotype, and moderately resistant MDR high CEM/VBL 100 T cells ( n =6). The transport of 3 H‐vinblastine, a strong multidrug resistance (MDR) substrate, and 3 H‐progesterone, a poor MDR substrate, was also studied. Results: Caco‐2 cells had a 2.4‐, 6.6‐, 6.7‐ and 1.03‐fold higher net basal to apical transport (efflux) of 3 H‐cortisol, 3 H‐ciclosporin, 3 H‐vinblastine and 3 H‐progesterone, respectively. PSC 833 (20 μ M ) reduced cortisol efflux by 69% (0.23 ± 0.04 to 0.07 ± 0.01 pmol/cm 2 /h, P < 0.05) and ciclosporin efflux by 76% (11.1 ± 1.4 to 2.7 ± 0.6 pmol/cm 2 /h, P < 0.001). MDR low CEM T cells had a 1.4‐, 1.9‐, 3.2‐ and 1.02‐fold higher intracellular accumulation of cortisol, ciclosporin, vinblastine and progesterone than MDR high CEM/VBL 100 T cells. Increasing concentrations of PSC 833 (> 0.1 μ M ) and verapamil (> 1 μ M ) restored the intracellular level of 3 H‐cortisol and 3 H‐ciclosporin in MDR high CEM/VBL 100 T cells to that of MDR low CEM cells with little change in accumulation in the MDR low parental cell line. Conclusions: P‐gp inhibitors significantly increase intracellular cortisol and ciclosporin levels in human intestinal epithelium and T lymphocytes in a dose‐dependent manner, demonstrating a potential mechanism for overcoming poor response to immunosuppressant therapy in refractory inflammatory bowel disease.