Biomedical Engineering Reference
In-Depth Information
A, PSC 833, PAK-104P, sulfinpyrazone, benzbromarone, and probenecid, in addi-
tion to Pgp, are reported to block MRP2 activity in intact cells. Many of the anionic
substrates of MRP2 (e.g., LTC
4
, phenolphtalein glucuronide, fluorescein, methotrex-
ate) can act as competitive inhibitors in in vitro systems.
319
,
385
Interestingly, certain
MRP2 modulators can inhibit MRP2-mediated transport of a number of substrates
(e.g., probenecid inhibits methotrexate transport by MRP2) but stimulate transport
of others (e.g., probenecid stimulates transport of taxanes, etoposide, vinblastin, and
HPIs).
244
,
367
,
368
,
386
,
387
Zelcer et al. demonstrated that a large variety of clinically used compounds could
stimulate MRP2 transport.
388
Fromm et al. reported that rifampicin is able to induce
intestinal MRP2 as well as Pgp in humans.
362
Regulation of MRP2 activity can also
take place at the cellular level. Dynamic endocytic retrieval and exocytic insertion
of MRP2 between the canalicular membrane and an intracellular pool of vesicles
are involved. Treatment of rats with lipopolysaccharide (which induces cholestasis)
also induces endocytic retrieval of MRP2.
389
,
390
Implications for the disposition of
substrate drugs of MRP2 are currently unknown.
In vitro, transcriptional regulation of MRP2 has also been characterized, and vari-
ous MRP2-inducing agents have been found. In primary cultures of human and/or rat
hepatocytes, dexamethasone, rifampicin, tamoxifen, cisplatin, cycloheximide, phe-
nobarbital, 2-acetaminofluorene, cholic acid, chenodeoxycholic acid, clotrimazole,
pregnenolone, sodium arsenite, and oltipraz, serving here as examples, induced MRP2
expression.
350
,
391
-
400
Induction of liver Mrp2 expression has also been described in
Wistar rats treated with St. John's wort.
400
Similarly, treatment of Sprague-Dawley
rats with dexamethasone induced Mrp2 expression in liver and kidney.
401
However,
further investigations are needed, as discrepancies have been reported between in
vitro and in vivo findings. For instance, in contrast with results observed in cultured
hepatocytes, phenobarbital treatment of rats did not increase Mrp2 expression.
402
-
404
Pharmacological and Toxicological Function
The pharmacological and toxicolog-
ical functions of MRP2 have been studied extensively in in vitro and in vivo models,
using rat strains defective for Mrp2 (GY/TR- and EHBR) and cells from humans
suffering from the Dubin-Johnson syndrome. In these models the pharmacokinetics
of MRP2 substrate compounds are altered significantly, suggesting that MRP2 can
affect the pharmacological behavior of these substrate drugs. MRP2 is involved in
the hepatobiliary excretion of clinically important anionic drugs and intracellularly
formed glucuronide and glutathione conjugates of many drugs,
352
,
354
,
372
,
405
thus play-
ing a key role in the phase III xenobiotic detoxification system, the biliar excretion of
conjugated metabolites produced by phase I and II hepatic enzymes. MRP2 probably
has a central role in the disposition and hepatobiliary elimination of substrate drugs.
In Mrp2-deficient rats, a reduction was found in the biliary excretion of cefodizime,
ceftriaxone, and grepafloxacin, antimicrobials used clinically in the treatment of in-
fections of the biliary tract, indicating that efficient excretion of these drugs into the
bile is probably mediated by MRP2.
379
,
406
-
408
Similarly, the biliary elimination of
the HMG-CoA reductase inhibitor pravastatin, a known MRP2 substrate, has been
reported to be threefold lower in EHBR than in normal rats.
409
Biliary excretion of
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