CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 770

to a compensation by other transporters), it has been suggested that those patients,
however, are at increased risk of drug-induced toxicity. 351 In rats, two differently
occurring mutations in the Mrp2 gene generate the Mrp2-deficient GY/TR − or Eisai
hyperbilirubinemic (EHBR) rat strains. 352 - 356 Recently, in a study performed in 64
Caucasian cancer patients, a functional MRP2 SNP (C3972T) able to affect irinotecan
pharmacokinetics has been found. Patients carrying the 3972T allele showed higher
AUC of irinotecan and its metabolite, SN-38 glucuronide. SNP analysis of MRP2
has also been performed in healthy Japanese subjects, in a Dutch population, and
in several cell lines established from surgically dissected tumors from Japanese pa-
tients. Several SNPs have been identified, and some of them have been characterized
functionally, but their clinical consequences and impact on drug disposition need
to be clarified. 15 , 286 , 350 , 357 , 358 Interindividual differences in the expression level of
MRP2 in liver and gut have also been found, and it is supposed that together with
single-nucleotide polymorphism, the induction/down-regulation of this transporter
can be affected by different disease states (e.g., cholestatic conditions, hepatitis) and
food and/or drug intake. 352 , 359 - 362 Clinical implications of this observation are not

yet known.

Main Substrate Classes (Clinically Applied) There are many similarities between
compounds transported by MRP2 and MRP1, although there is not complete over-
lap. Anticancer drugs transported by MRP2 include anthracyclines (doxorubicin
and epirubicin), camptothecin derivatives (irinotecan/SN-38), Vinca alkaloids (vin-
blastin and vincristine), mitoxantrone, cisplatin, and probably, etoposide. 244 , 296 , 363 - 367
Recently, it has been reported that MRP2 transports taxanes (paclitaxel and doc-
etaxel) and that this transport is stimulated by probenecid. 368 Like MRP1 and MRP3,
MRP2 is able to confer resistance after short-term (brief) exposure to high con-
centrations of methotrexate. 244 , 248 , 369 In addition, as MRP2 is primarily an organic
anion transporter, it seems very likely that basic drugs (e.g., vinblastin) are cotrans-
ported with GSH. 363 , 367 , 370 Substrates of MRP2 also include many amphipathic anion
drugs and endogenous compounds and GSH, glucuronide, and sulfate conjugates.
MRP2 is the principal transporter of bilirubin mono- and bisglucuronides into the
bile. 371 , 372 Other MRP2 endogenous substrates include LTC 4 , reduced and oxidized
GSH (GSSG), LTD 4 ,LTE 4 , estradiol-17 -glucuronide, L-thyronine, and glucuronide

conjugates of such drugs as diclofenac and acetaminophen. 350 , 373 - 375 Taurolitho-
cholate sulfate and taurochenodeoxycholate sulfate are also substrates of MRP2. 376 , 377
Other clinically important drugs transported by MRP2 are pravastatin; temocapri-
lat; ampicillin; ceftriaxone; grepafloxacin and its glucuronide conjugate, BQ-123;
sulfinpyrazone; the HIV protease inhibitors saquinavir, ritonavir, and indinavir;
p -aminohippurate; and possibly, arsenic trioxide. 296 , 367 , 378 - 381 Furthermore, MRP2
has been shown to mediate the transport of some carcinogens, such as PhIP (2-amino-
1-methyl-6-phenylimidazo[4,5- b ]pyridine), 382 , 383 the glucuronide conjugate of the
nicotine metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 307

the

fungal toxin ochratoxin A, 384 arsenite, cadmium, and -naphthylisothiocyanate. 370 , 381

Inhibitors and Inducers Inhibitors of MRP2 have been described, but they are not
highly specific. MK571 inhibits MRP2 but also MRP1 and MRP3, and cyclosporin