P-glycoprotein, multidrug resistance-related proteins (MRPs) and lung resistance-related protein (LRP) are involved in multidrug
resistance in tumor cells but are also expressed in normal tissues. In the LLC-PK1 tubular renal cell line, a 15-day treatment with 25 AM
rifampicin significantly increased the mRNA levels of P-glycoprotein, MRP1, MRP2, LRP and cytochrome P450 3A4 (CYP 3A4). Western
blot analysis confirmed a moderate increase in the expression of P-glycoprotein and MRP2, but not MRP1 also at the protein level. The
intracellular uptake of doxorubicin was significantly lower in rifampicin pretreated cells. A pretreatment with 6-[82S,4R,6E)-4-methyl-2-
(methylamino)-3-oxo-6-octenoic acid]cyclosporin D, valspodar (PSC 833), a specific inhibitor of P-glycoprotein, with (3-(3-(2-(7-chloro-2-
quinidinyl)ethenyl-phenyl)((3-diimethyl amino-3oxo propyl)thio)methyl)thio)propanoic acid, sodium salt (MK-571), a specific inhibitor of
MRP1, and with verapamil, that inhibits both proteins, significantly increased doxorubicin cell accumulation in rifampicin pretread cells. In
rifampicin treated cells cultured on porous membranes, doxorubicin showed a polarized transport, that was reduced by a pretreatment with
PSC 833. A chronic treatment with rifampicin induces the expression of transport proteins and of CYP 3A4 and could therefore alter the renal
elimination kinetics of drugs that are their substrates.
