Biomedical Engineering Reference
In-Depth Information
As reported above, induction of hepatic Mrp3 by phenobarbital is one of the
most important mechanisms involved in the reduction of the biliary excretion of ac-
etaminophen glucuronide after phenobarbital pretreatment of rats.
374
Phenobarbital is
a well-known enzyme inducer that also induces the hepatocyte basolateral transporters
Mrp3 and organic anion-transporting polypeptide 2 (Oatp2) in Sprague-Dawley
rats.
374
,
470
,
477
Studies of the recirculating isolated perfused rat liver model have sug-
gested that Mrp3 is involved in the basolateral transport of AP-G. Experiments with
plasma inside-out membrane vesicles showed that AP-G is a low-affinity substrate for
Mrp2 and Mrp3 and that
p
-hydroxyphenobarbital glucuronide (
p
-OHPBG), a major
phenobarbital metabolite, significantly inhibited Mrp2- and Mrp3-mediated transport
processes.
373
These findings support the hypothesis that the impaired biliary excretion
of AP-G after phenobarbital pretreatment can be attributed primarily to the induction
of hepatic Mrp3.
MRP4
MRP4 substrates include cyclic nucleotides and nucleotide analogs widely
used in antiviral and anticancer therapy [e.g., 9-2-phosphonylmethoxyethyladenine
(PMEA), azydothymidine (AZT) lamivudine, 2
,3
-dideoxy-3
-thiacytidine, ganci-
clovir, 6-mercaptopurine, thioguanine, cladribine],
478
-
483
cyclic GMP (guanosine
3
-5
-cyclic monophosphate) and AMP (adenosine 3
-5
-cyclic monophosphate),
methotrexate, leucovorin,
249
,
478
cyclophosphamide,
484
several camptothecins (topote-
can, irinotecan, its active metabolite SN-38, and rubitecan),
484
-
486
GSH, and
folate.
246
,
249
,
484
,
487
,
488
The involvement of GSH in MRP4 cotransport of certain
substrates is still controversial, as different groups reported contradicting
results.
479
,
487
,
489
Several drugs have been reported to inhibit MRP4 activity efficiently
in vitro, but their specificity and clinical applicability are still unclear. Buthionine-
sulfoximine (BSO), MK571, celecoxib, and diclofenac as well as dipyridamole, di-
lazep, nitrobenzyl, mercaptopurine ribozide, probenecid, and sulfinpyrazone have
been described as MRP4 blockers.
481
,
484
Little is known about induction of MRP4
expression. Recently, a study in infected human macrophages indicated that AZT
treatment induced MRP4 mRNA expression.
490
The pharmacological role of MRP4 is not yet completely known. However, due
to the broad tissue distribution of MRP4, it is likely that its modulation by coadmin-
istered drugs (inhibitors or inducers) may have important pharmacokinetic implica-
tions for substrate drugs. In this respect, a recent and interesting study from Leggas
et al.
491
reported enhanced accumulation after intravenous administration of topote-
can (a MRP4 substrate) in brain tissue and cerebrospinal fluid (CSF) of Mrp4
(
−
/
−
)
mice compared with Mrp4
(
+
/
+
)
mice. Moreover, in a previous study,
492
the transport
of intraventricularly injected methotrexate from the choroid plexus into the blood
circulation was inhibited by probenecid, a reported Mrp4 inhibitor. Therefore, Mrp4
appears to play a significant role in brain penetration of selected cytotoxins and other
therapeutic agents. Modulation of MRP4 activity and expression may enhance brain
penetration of drugs, thus possibly improving the treatment of primary brain tumors
and other cerebral diseases. At the cellular level, inhibition of MRP4 activity may be
a useful strategy to increase the intracellular concentration of drugs, thus overcom-
ing drug resistance. Interestingly, the expression level of MRP4 was associated with
poor prognosis in patients with neuroblastoma.
486
Moreover, in a preclinical study,
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