TY - JOUR
T1 - Rapid induction of P-glycoprotein expression by high permeability compounds in colonic cells in vitro
T2 - a possible source of transporter mediated drug interactions?
AU - Collett, Andrew
AU - Tanianis-Hughes, Jolanta
AU - Warhurst, Geoff
PY - 2004/8/15
Y1 - 2004/8/15
N2 - P-glycoprotein (PGP) substrates with high membrane permeability, such as propranolol and verapamil, are considered to be essentially " transparent" to PGP since the transporter does not significantly limit their absorption or elimination. However, the question of whether such compounds can modulate PGP expression in epithelial cells following short-term exposure, with potential consequences for drug interactions, has not been addressed. LS180 colonic epithelial cells were exposed to propranolol or verapamil at concentrations (50-300 μM) consistent with those likely to be present in the gut lumen during oral dosing. Both compounds stimulated four to six-fold increases in MDR1 mRNA and PGP protein expression measured by quantitative real-time PCR and immunoblotting, respectively. These changes were accompanied by an induction in transporter activity measured by rhodamine 123 efflux. In contrast, metoprolol, a compound with similar permeability but no affinity for PGP had no effect on PGP expression. The induction of PGP by propranolol and verapamil was rapid with significant increases occurring within 3 h with maximal stimulation after 6 h exposure. Rifampicin, shown to cause clinical drug interactions via a PXR-mediated increase in PGP expression, exhibited a very similar time-course and extent of induction. In conclusion, verapamil and propranolol, whose trans-epithelial permeability are unaffected by PGP, appear to be effective inducers of PGP expression in gut epithelial cells in vitro. While the in vivo significance of these observations is unknown, this questions whether high permeability, "PGP-transparent" compounds, currently favoured in drug selection strategies, should be evaluated in terms of their potential for transporter-mediated drug interactions.
AB - P-glycoprotein (PGP) substrates with high membrane permeability, such as propranolol and verapamil, are considered to be essentially " transparent" to PGP since the transporter does not significantly limit their absorption or elimination. However, the question of whether such compounds can modulate PGP expression in epithelial cells following short-term exposure, with potential consequences for drug interactions, has not been addressed. LS180 colonic epithelial cells were exposed to propranolol or verapamil at concentrations (50-300 μM) consistent with those likely to be present in the gut lumen during oral dosing. Both compounds stimulated four to six-fold increases in MDR1 mRNA and PGP protein expression measured by quantitative real-time PCR and immunoblotting, respectively. These changes were accompanied by an induction in transporter activity measured by rhodamine 123 efflux. In contrast, metoprolol, a compound with similar permeability but no affinity for PGP had no effect on PGP expression. The induction of PGP by propranolol and verapamil was rapid with significant increases occurring within 3 h with maximal stimulation after 6 h exposure. Rifampicin, shown to cause clinical drug interactions via a PXR-mediated increase in PGP expression, exhibited a very similar time-course and extent of induction. In conclusion, verapamil and propranolol, whose trans-epithelial permeability are unaffected by PGP, appear to be effective inducers of PGP expression in gut epithelial cells in vitro. While the in vivo significance of these observations is unknown, this questions whether high permeability, "PGP-transparent" compounds, currently favoured in drug selection strategies, should be evaluated in terms of their potential for transporter-mediated drug interactions.
KW - Drug absorption
KW - Drug permeability
KW - LS-180 cells
KW - P-glycoprotein
KW - Transporter induction
UR - http://www.scopus.com/inward/record.url?scp=3242686014&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2004.05.006
DO - 10.1016/j.bcp.2004.05.006
M3 - Article
C2 - 15276086
AN - SCOPUS:3242686014
VL - 68
SP - 783
EP - 790
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 4
ER -