CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 773

transport of 2,4-dinitrophenyl- S -glutathione, a MRP2 substrate, in EHBR compared
with normal rats. 430 , 431
Extrapolating these findings to the known MRP2 drug substrates, it is likely that
these compounds are also affected by intestinal MRP2 activity in their oral bioavail-
ability and direct intestinal excretion. It is also possible that in some studies the
overlapping transport activity of the highly expressed intestinal transporters Pgp and
BCRP has masked the relevance of MRP2 in this function. 432 Recently, in preclin-
ical studies using Wistar and TR − rats, MRP2 has been reported to limit the oral
bioavailability of the HIV protease inhibitor saquinavir 433 and of the taxanes pacli-
taxel and docetaxel, substrates for which both Pgp and MRP2 have affinity. 368 , 380 , 433
In addition, recent research demonstrates that MRP2 modulates the brain penetration
of clinically important substrate drugs. In TR − rats, brain extracellular levels and the
anticonvulsant effect of the antiepileptic drug phenytoin were significantly increased
compared with normal rats. Moreover, using in vivo microdialysis in rats, a signifi-
cantly enhanced brain extracellular concentration of phenytoin has been reported with
local perfusion of the anion transporter inhibitor probenecid. 434 - 436 A significant in-
crease of drug penetration into the brain by probenecid was reported previously for
valproate 437 and carbamazepine 438 and has been attributed to inhibition of MRP2 in
the blood-brain barrier, although probenecid is not a specific inhibitor of MRP2. 439
Subsequently, a study using TR − rats reported increased anticonvulsant response to
carbamazepine in the kindling model of temporal lobe epilepsy, but no difference
in brain drug levels. 435 These findings have important clinical relevance, as recently
it has been hypothesized that overexpression of Pgp and MRPs may be involved in
the generation of drug resistance in epileptic patients. 14 , 440 - 442 Therefore, the de-
velopment of active and more specific MRPs and/or Pgp inhibitors might overcome
drug resistance to antiepileptic drugs. 443 Furthermore, due to the broad MRP2 sub-
strate specificity, its pharmacological role and the wide range of clinically used drugs
that can modulate MRP2 activity, several clinically relevant drug-drug interactions
mediated by MRP2 could be anticipated.
Clinically relevant drug-drug interactions have been described when rifampicin
is coadministered with morphine or propafenone, resulting in loss of analgesic effect
of morphine or in reduced bioavailability of propafenone, respectively. 444 - 446 These
interactions can be attributed in part to induction of intestinal Pgp and phase I drug-
metabolizing enzymes. However, rifampicin has also been demonstrated to induce
the intestinal expression and activity of MRP2. 362 Therefore, induction of MRP2
expression mediated by rifampicin could contribute to the reduction in intestinal
absorption, plasma concentrations, and urinary recovery of morphine and propafenone
that has been observed.
A drug-drug interaction has also been described between phenobarbital and ac-
etaminophen glucuronide: Pretreatment with phenobarbital significantly increased
acetaminophen glucuronide (AP-G) formation but significantly reduced AP-G bil-
iary excretion in rats, 447 whereas acute phenobarbital treatment decreased the biliary
excretion of AP-G together with a moderate reduction in AP-G production. 448 The
decreased biliary excretion of AP-G due to phenobarbital treatment can be attributed