CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 774

to impairment in biliary excretion or up-regulation in basolateral transport of AP-G.
Although the impaired biliary excretion of AP-G after phenobarbital pretreatment
may be attributed primarily to the induction of hepatic MRP3 by phenobarbital (see
below), it could also be explained by inhibition of Mrp2-mediated AP-G transport
by the phenobarbital metabolite p -hydroxyphenobarbital glucuronide ( p -OHPBG). 374
Pharmacokinetic modeling and simulation studies suggest that the biliary excretion
of AP-G is mediated almost exclusively by Mrp2. 373 Furthermore, the AP-G biliary
clearance was markedly decreased and the AP-G basolateral clearance significantly
increased in TR − rat liver. In plasma membrane vesicles, p -OHPBG significantly

inhibited Mrp2. 374
Another drug-drug interaction has been reported between probenecid and the
HIV protease inhibitor (HPI) saquinavir and the anticancer drug paclitaxel. In in
vitro experiments MRP2 appears to transport saquinavir and paclitaxel efficiently
and the transport of both drugs is stimulated by probenecid. 314 , 368 , 380 In wild-type
and Pgp deficient mice (used because saquinavir and ritonavir are also good Pgp sub-
strates), coadministration of saquinavir, ritonavir (to inhibit saquinavir metabolism),
and probenecid resulted in strongly decreased saquinavir plasma levels. 435 Although
the same experiment performed in Mrp2-deficient rats showed that Mrp2 transport
function was not the main cause for the decreased HPI plasma levels, it cannot be ex-
cluded that in vivo there may be MRP2 stimulation that contributes to this drug-drug
interaction. As probenecid is still used in general clinical practice in some countries,
in particular in HIV/AIDS patients, for treatment of gout or in adjunct to antimicro-
bial therapy (e.g., with penicillin and/or cephalosporins) to boost antibiotic plasma
concentrations, this reported drug-drug interaction possibly has clinical conse-
quences. It may lead to a drop in HPI plasma levels, resulting in suboptimal therapy;
selection of mutant, resistant HIV strains; and subsequently, to failure of therapy. Sim-
ilarly, coadministration of probenecid and other MRP2-stimulating drugs in cancer
patients during chemotherapy with MRP2 substrate drugs (e.g., taxanes, etoposide)
might enhance MRP2-mediated drug resistance, increase the elimination of parenter-
ally administered drugs, and decrease the oral bioavailability of anticancer drugs, with
potential effects on therapeutic efficacy. 368 It is noteworthy that recently, consider-
ably high levels of MRP2 have been reported in cancers originating from lung, breast,
ovarian, renal, and colon carcinomas. 449 To date there is no clinical evidence of the
aforementioned drug interaction with probenecid; however, selected combinations
are worth investigating.
Furthermore, Zelcer et al. and Bakos et al. recently reported a broad range of
clinically applied drugs that can stimulate and/or inhibit MRP2 activity in vitro,
thus potentially leading to clinically relevant (beneficial or adverse) drug-drug
interactions. 319 , 388 Indomethacin, penicillin G, pantoprazole (as well as other proton
pumps inhibitors, such as omeprazole and lansoprazole), furosemide, glibenclamide
and sulfanitran stimulated MRP2 transport in in vitro models. However, based on
the complex model of the MRP2 interaction proposed (two distinguishable binding
sites, one site from which the drug is transported and a second site that regulates the
former allosterically), the effect of a transport modulator appeared to depend on the
substrate transported. For example, probenecid significantly stimulated transport of