CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 772

methotrexate, mediated by MRP2 as well as BCRP, has been proposed to be responsi-
ble for its intestinal toxic effects. 45 , 410 Furthermore, secretion into the bile via MRP2
of the glucuronide derivative of the nonsteroidal anti-inflammatory drug diclofenac
is supposed to cause toxic effects to the bile canalicular membrane. 376
Moreover, MRP2, together with BCRP and Pgp, may contribute to the gastrointesti-
nal excretion of the anticancer drug irinotecan and its metabolites SN-38, and SN-38
glucuronide. Irinotecan, SN-38, and SN-38 glucuronide are transported by BCRP and
to a lesser extent by MRP2 and Pgp. 197 , 199 , 411 , 412 The intestinal excretion of irinote-
can and its metabolites has been linked to severe unpredictable diarrhea, a frequent
dose-limiting effect of irinotecan that shows wide interpatient variability. 310 , 413 - 419
Several strategies to prevent this important toxicity using efficient inhibitors of the
gastrointestinal transport of irinotecan and its metabolites have been investigated.
In rats, coadministration of probenecid (a MRP2 inhibitor) reduced SN-38 biliary
excretion and decreased irinotecan-induced late-onset diarrhea. 378 , 420 In other stud-
ies, coadministration of irinotecan with cyclosporin A (a Pgp, BCRP, and MRP2
inhibitor) 240 , 421 resulted in significantly reduced excretion of irinotecan and SN-38
via the biliary route and/or the intestinal route in rats. 422 , 423 In patients affected by
fluorouracil-refractory metastatic colorectal cancer, a clinical phase I study of intra-
venous irinotecan and oral cyclosporin A revealed an increased plasma AUC 0 - 24h of
irinotecan, SN-38, and SN-38 glucuronide, and a reduction of irinotecan clearance
and of diarrhea with preservation of antitumor activity. 424 Similar results were found
in another study performed in a larger patient population with refractory solid tumors
or lymphoma. 425
MRP2-mediated biliary excretion of drugs as part of a multiple elimination path-
way (such as biliary and urinary) has been proposed to confer pharmacokinetic ad-
vantage to substrate drugs (e.g., temocapril), thus avoiding potentially toxic effects. In
patients with renal failure, the relatively stable pharmacokinetics of temocaprilat [the
active metabolite of the angiotensin-converting enzyme (ACE) inhibitor temocapril],
compared with other ACE inhibitors (such as enalapril, captopril, and cilazapril),
is thought to be due to its dual excretion via both bile and urine, 426 - 429 whereas the
other ACE inhibitors are eliminated primarily via renal excretion. Preclinical findings
show that temocaprilat is transported by MRP2 and that MRP2 is the predominant
factor in determining its biliary excretion. The biliary clearance after intravenous
administration of temocaprilat was significantly lower in EHBR than in Sprague-
Dawley rats. In contrast, the other ACE inhibitors do not appear to be good MRP2
substrates. 430 In addition, intestinal MRP2 limited the oral bioavailability of substrate
compounds. In preclinical studies, absorption after oral administration and the tissue
levels in several organs (liver, kidney, lung, and colon) of the food-derived carcinogen
PhIP (a proven MRP2 substrate) were approximately twofold higher in TR − than in
Wistar rats. Furthermore, after intravenous administration, the levels of PhIP and its
metabolites in bile and the direct intestinal excretion of unmetabolized PhIP were
significantly reduced in TR − compared with Wistar rats. 370 , 382 In vitro experiments
using reverted sacs prepared from jejunum and the ussing chamber have shown an
important reduction of clearance by intestinal excretion and vectorial transcellular