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Stimulation of P‐GP mediated transport & expression by flutamide in vitro
Author(s) -
Bertelsen K. M.,
Moltke L. L.,
Greenblatt D. J.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.055
Subject(s) - flutamide , in vitro , stimulation , receptor , pharmacology , mifepristone , tamoxifen , medicine , endocrinology , prostate cancer , androgen receptor , western blot , androgen , hormone , biology , cancer , biochemistry , breast cancer , pregnancy , genetics , gene
Aims Steroid receptor antagonists, such as tamoxifen (TAM) or mifepristone (MFP), display significant inhibition of the ABC transport protein P‐glycoprotein (P‐gp) in vitro . To date, interactions between androgen receptor antagonists have yet to be described. Given their common use as treatments for prostate cancer, interactions between androgen receptor antagonists and P‐gp may be important. Methods Two in vitro models of drug transport were used to assess the effects of flutamide (FLU) on drug transport. Possible modulation of P‐gp expression was also investigated. Results Acute FLU treatment stimulated transport of Rho‐123 in Caco‐2 monolayers (P App(B→A/A→B) Control: 5.8±1.2, 100.0 μM FLU: 10.5±1.0). These observations were confirmed using a Rho‐123 retention assay within LS180V cells. As positive controls, TAM and MFP displayed inhibition in both models. After 72‐hour incubation with LS180V cells, only FLU resulted in enhanced immunoreactivity of P‐gp after Western blot analysis. Conclusions In contrast to TAM and MFP, these data suggest that FLU stimulates P‐gp activity and expression. Whether in vitro models used in these studies are representative of prostate tissues remains unclear. Nonetheless, considering that MDR1 expression within prostatic neoplasms remains a clinically significant issue, the stimulatory effects noted with FLU on P‐gp function and expression may have clinical implications. Clinical Pharmacology & Therapeutics (2005) 77 , P42–P42; doi: 10.1016/j.clpt.2004.12.055