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NEUROPHARMACOLOGY
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany
Received for publication
January 31, 2003
Accepted
March 13, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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). These efflux pumps are expressed widely in various
tissues and serve as defense mechanisms limiting tissue accumulation of
naturally occurring toxins, xenobiotics, and drugs
(Silverman, 1999). Of the
current 12 members of the MRP family, MRP2 (ABCC2) is considered the major
mammalian membrane transporter responsible for the secretion of bilirubin
glucuronides from liver to bile (Gerk and
Vore, 2002; Meier and Stieger,
2002). More recently, MRP2 has been found in the apical (luminal)
membrane of brain capillary endothelial cells in fish, rats, pigs, and humans,
implicating MRP2 in drug transport from brain to blood
(Miller et al., 2000;
Dombrowski et al., 2001;
Miller et al., 2002).
Endothelial cells of brain capillaries, containing tight junctions and bipolar
differential expression of transporters, maintain the blood-brain barrier
(BBB) (Lee et al., 2001).
However, although the role of Pgp as a gatekeeper in the BBB is well
established, limiting entry of drugs and toxins into the brain
(Schinkel, 1999), the role of
MRP2 in regulating drug permeability across the BBB is defined poorly. Using
cDNA arrays, a 225% increase in MRP2 gene expression was found in brain
capillary endothelial cells from patients with drug resistant temporal lobe
epilepsy (TLE), suggesting that MRP2 expression changes may play an important
role in resistance to antiepileptic drugs (AEDs) by decreasing the
permeability of AEDs across the BBB
(Dombrowski et al., 2001).
However, there is no direct evidence that AEDs or other centrally acting drugs
are transported by MRP2 in the BBB.
In the present study, we used three different strategies to study the
contribution of MRP2 to BBB function in rats. First, the MRP1/MRP2 inhibitor
probenecid (Gerk and Vore,
2002; Scheffer and Scheper,
2002) was used to study whether MRP2 inhibition in the BBB
increases extracellular brain levels of AEDs as determined by microdialysis
via probes in the cerebral cortex, which contains high levels of MRP2 mRNA
(Cherrington et al., 2002).
Second, we used MRP2-deficient TR– rats
(Jansen et al., 1985;
Paulusma et al., 1996) to
determine whether the absence of MRP2 in the BBB of these rats
(Miller et al., 2000) leads to
an increased penetration of AEDs into the brain. Third, the kindling model of
TLE (Sato et al., 1990) was
used to study whether inhibition of MRP2 or lack of MRP2 in the BBB enhance
anticonvulsant activity of major AEDs.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). After a recovery period of at least 3 days (to allow the
BBB to reseal; Benveniste and Hansen,
1991) and 14 to 16 h before the experiment, a 3-mm microdialysis
probe (diameter 0.5 mm; CMA/12; Carnegie Medicine) was inserted through the
guide cannula to a depth of 5.0 mm from bregma into the frontal cortex of
conscious rats. Each rat was placed in a freely moving system, consisting of a
plastic cylinder with counterbalancing arm carrying a two-channel swivel
(Carnegie Medicine). The probe was perfused with mock cerebrospinal fluid (25
mM NaHCO3, 122 mM NaCl, 1.2 mM MgSO4, 3 mM KCl, 1.3 mM
CaCl2 and 0.4 mM H2KO4P, pH 7.4) at a flow
rate of 2 µl/min with a syringe pump (Carnegie Medicine). Each 40-µl
outflow sample was collected for drug analysis. One hour after onset of
perfusion, an AED (either phenytoin or phenobarbital) was administered i.p.
and dialysate samples (2/h) were collected over the next 2 h. The doses of
phenytoin (50 mg/kg) and phenobarbital (30 mg/kg) were chosen on the basis of
previous experiments in female Wistar rats
(Potschka and Löscher,
2001a; Potschka et al.,
2002), showing that these doses in rats result in plasma levels
similar to the "therapeutic range" known from patients with
epilepsy. Together with each dialysate sample, a blood sample was collected
from the periorbital plexus (after local anesthesia of the eye with a 2%
solution of tetracaine) for drug analysis in plasma and dialysate by
high-performance liquid chromatography as described previously
(Potschka and Löscher,
2001a; Potschka et al.,
2002). For inhibition of MRP2 in the BBB, local administration of
probenecid (10 mM dissolved in the perfusion solution) via one microdialysis
probe was started 30 min before AED injection. The other microdialysis probe
was perfused with mock cerebrospinal fluid only and served as individual
control in each rat. For each microdialysis probe used for the in vivo
experiments, in vitro drug recovery was determined before and after the in
vivo experiment and used for correction of the in vivo dialysate
concentrations as described previously
(Potschka and Löscher,
2001a). For in vivo experiments in Wistar rats, two probes were
used in combination (for left and right cortex), with recovery values not
differing by more than 5%. On conclusion of each experiment, the correct
location of the microdialysis probe in the frontal cortex was verified
histologically as described previously
(Potschka and Löscher,
2001a). In all rats used in this article, the probes were
correctly located in the left and right cortex. Furthermore, there was no
indication for any obvious neurodegeneration around the tip of the probe other
than that caused by the probe itself. In addition to microdialysis experiments in normal Wistar rats, adult MRP2-deficient TR– Wistar rats were used for microdialysis of phenytoin and phenobarbital as described above, except that microdialysis was performed from only one hemisphere. The TR– rats were bred in our department; breeding pairs were kindly provided by Prof. R. P. J. Oude Elferink (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands). For comparison with TR– rats, age-matched rats of the Wistar background strain (Harlan Netherland, Horst, The Netherlands) were used.
The statistical significance of differences between left and right cortex in normal Wistar rats was calculated by two-way analysis of variance (ANOVA) for repeated measurements followed by post hoc testing with the Wilcoxon test for paired replicates. Significance of differences between TR– rats and background strain was calculated by two-way ANOVA followed by the Mann-Whitney U test.
Kindling Model. Adult Wistar rats (nonmutant or MRP-deficient
TR– rats) were chronically implanted with a bipolar electrode into the
right basolateral amygdala (AP, –2.2; L, 4.8; V, 8.5 in Wistar rats from
Harlan-Winkelmann; AP, –2.2; L, 5.0; V, 8.3 in TR– rats and Wistar
rats from Harlan Netherland) as described previously
(Potschka and Löscher,
2002). Electrical stimulation of the amygdala was initiated after
a recovery period of 2 weeks after surgery. Kindling was performed by amygdala
stimulations which were applied once daily for 1 s with a stimulus strength of
330 µA (using 1-ms monophasic square-wave pulses, 50 Hz) until at least 10
consecutive fully kindled stage 5 seizures according to Racine
(1972) were elicited. In these
fully kindled rats, the anticonvulsant effect of phenytoin and phenobarbital
was assessed either alone or after pretreatment with probenecid (administered
15 min before the AEDs) by determining the threshold for generalized (stage
4/5) seizures (GST) 2 to 3 days before (vehicle control) and 60 min after AED
administration in the same groups of rats. The GST is a sensitive measure of
drug effects in individual kindled rats and often used for determining the
activity of anticonvulsant drugs (Croucher
and Bradford, 1991; Attwell et
al., 1998; Löscher et
al., 2000; Gernert and
Löscher, 2001).
For dose selection of probenecid, different doses (50, 100, and 200 mg/kg)
were administered alone and GST was determined after 75 min. Because 100 and
200 mg/kg, but not 50 mg/kg, probenecid induced significant GST increases, a
dose of 50 mg/kg was used for combination experiments with AEDs. For
phenytoin, different doses (6.25, 12.5, 25, and 50 mg/kg) were administered,
and dose selection was based on these dose-response experiments (see
Results). Similarly, different doses of phenobarbital (2.5, 5, 10,
and 30 mg/kg) were tested for dose selection (see Results). GST was
determined by a staircase procedure as described previously
(Gernert and Löscher,
2001). Blood was sampled immediately after GST determination for
AED analysis in plasma (Potschka and
Löscher, 2001a; Potschka
et al., 2002). In addition to GST determinations, rats were
observed for drug adverse effects, including the rotarod test, as described
previously (Gernert and Löscher,
2001). The statistical significance of differences between drug
treatments in the same group of rats was calculated by the Wilcoxon test for
paired replicates. Significance of differences between TR– rats and
background strain was calculated by the U test.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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) and is thought to be predominantly expressed in brain
parenchyma and not in endothelial cells of the BBB
(Regina et al., 1998;
Decleves et al., 2000),
inhibition of MRP1 by probenecid was not considered a bias for the present
experiments. Using in vivo brain microdialysis in conscious rats,
extracellular brain levels of phenytoin have recently been shown to be
significantly increased by local application of probenecid via the dialysis
probe (Potschka and Löscher,
2001b), so that phenytoin was chosen as a drug apparently being
subject to transport by MRP2. From preliminary experiments with various AEDs
(carbamazepine, phenobarbital, lamotrigine, and felbamate), phenobarbital was
chosen because its brain penetration was not affected by probenecid. The
comparison between phenytoin and phenobarbital is shown in
Fig. 1. The intracerebral
administration of probenecid did not alter the plasma levels of phenytoin or
phenobarbital, but significantly increased the extracellular brain level and
the dialysate/plasma ratio of phenytoin, but not of phenobarbital.
|
BBB Permeability in MRP2-Deficient TR— Rats. To validate the data from the experiments with MRP2 inhibition by probenecid, brain penetration of phenytoin and phenobarbital was compared between MRP2-deficient TR– Wistar rats and the normal Wistar background strain. Phenytoin levels in plasma or decay of plasma phenytoin levels did not differ significantly between mutant rats and background strain, whereas phenobarbital levels in plasma of TR– rats were slightly lower compared with normal rats (Fig. 2). Phenytoin reached higher extracellular brain levels in TR– rats compared with nonmutant rats (analysis by ANOVA indicated a significant difference with P = 0.0237), resulting in a significantly higher dialysate/plasma ratio in MRP2-deficient rats. No such difference was seen for phenobarbital, thus substantiating the results from MRP2 inhibition by probenecid.
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Effect of MRP2 Inhibition on AED Efficacy in Kindled Rats. An
increase in extracellular brain levels of phenytoin by inhibition of MRP2
should be associated with increased anticonvulsant activity because it is the
extracellular level that is thought to be relevant for phenytoin's
anticonvulsant action (Rogawski and
Porter, 1990). Fully kindled rats were used to study whether
probenecid potentiates phenytoin's anticonvulsant effect. First, different
i.p. doses of probenecid (ranging from 50 to 200 mg/kg) were tested in kindled
rats to select a dose that does not exert a significant effect on seizure
threshold when given alone. A dose of 50 mg/kg was chosen from these
experiments (Fig. 3A). This
dose of probenecid was then injected i.p. 15 min before phenytoin to study
whether this results in an enhanced anticonvulsant activity of the AED.
Phenytoin was administered at a dose (6.25 mg/kg), which alone did not exert
any significant anticonvulsant effect (Fig.
3A). As shown in Fig.
3A, the combination of probenecid and phenytoin resulted in a
marked anticonvulsant effect, in that the seizure threshold was significantly
increased by 90%. To obtain such a threshold increase with phenytoin alone,
the dose of phenytoin had to be more than doubled, as determined by
dose-response experiments (data not shown). Higher doses of probenecid alone
(100 or 200 mg/kg) significantly increased GST by only about 60% without any
clear dose-response (data not shown). Thus, it is highly unlikely that the
large GST increase obtained after combined treatment with subanticonvulsant
doses of probenecid and phenytoin (Fig.
3A) was just a result of an additive effect apart from any effect
on brain phenytoin transport. Furthermore, plasma levels of phenytoin were not
affected by i.p. administration of probenecid
(Table 1), so that the
significant increase of anticonvulsant efficacy was most likely related to
enhanced penetration of phenytoin into the brain because of MRP2 inhibition in
the BBB. No behavioral adverse effects were observed at the combination of
probenecid and phenytoin, and all rats passed the rotarod test. The finding
that probenecid increased the anticonvulsant efficacy but not the toxicity of
phenytoin can be explained by the fact that behavioral adverse effects,
including rotarod failures, are only observed after much higher doses or brain
levels of phenytoin. Thus, even at 12.5 or 25 mg/kg phenytoin, no central
nervous system toxicity is observed in the Wistar rats used in this study
(data not shown).
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|
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AED Efficacy in MRP2-Deficient TR— Rats. To substantiate the effect of MRP2 inhibition in the kindling model, MRP-2 deficient TR– rats were kindled, and the anticonvulsant effect of phenytoin and phenobarbital was compared in kindled TR– Wistar rats and kindled rats of the normal Wistar background strain. Although plasma levels of phenytoin were slightly lower in TR– compared with nonmutant rats (Table 1), phenytoin was much more effective to increase seizure threshold in TR– rats (Fig. 4A), substantiating that inhibition or lack of MRP2 in the BBB results in a functionally relevant increase in brain levels of this major AED. Adverse effects of phenytoin (slight ataxia) were not different between TR– rats and controls, and all rats passed the rotarod test. In contrast to findings with phenytoin, no significant difference in anticonvulsant activity of phenobarbital was found between MRP2-deficient and normal Wistar rats (Fig. 4B).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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) as a hepatic anion
transport-deficient ("TR–") rat strain, has a
single-nucleotide deletion in the MRP2 gene, resulting in the absence of the
gene product from the canalicular membrane of hepatocytes
(Paulusma et al., 1996), so
that this mutant rat is widely used to study the role of MRP2 in hepatobiliary
excretion of organic anions (König et
al., 1999). However, recently Miller et al.
(2000) reported that MRP2 is
also absent in brain capillary endothelial cells of TR– rats, which
prompted us to use these rats for the present experiments.
To our knowledge, the present data are the first to demonstrate a role of
MRP2 in BBB function in vivo. In line with the present results on phenytoin,
recent in vitro experiments in isolated capillaries from rat, pig, and fish
brain using MRP2 modulators such as leukotriene C4 have indicated that MRP2
contributes substantially to the active barrier function of the endothelium
(Miller et al., 2000,
2002;
Fricker et al., 2002). The
localization of MRP2 to the luminal surface of the brain capillary endothelium
(Miller et al., 2000), and the
wide spectrum of drugs accepted as substrates by MRP2
(Borst et al., 1999;
Leslie et al., 2001;
Gerk and Vore, 2002) implicate
that this transporter may be as important as Pgp in BBB function. Furthermore,
the finding that phenytoin is subject to transport by Pgp
(Potschka and Löscher,
2001a; Rizzi et al.,
2002) and MRP2 in the BBB demonstrates that MRP2 and Pgp have an
overlapping substrate spectrum, which is known from substrate recognition
studies on Pgp and MRPs (Lee et al.,
2001). The limitation of phenytoin's access to the brain by Pgp
and MRP2 might explain why phenytoin reaches its peak anticonvulsant effect
less rapidly than most other AEDs, at least in rodents
(Löscher et al.,
1991).
In addition to a role of MRP2 in normal functioning of the BBB, it has been
suggested that overexpression of MRP2 may be involved in the drug
refractoriness of patients with TLE
(Dombrowski et al., 2001),
which was the reason to chose AEDs and the kindling model of TLE for the
present experiments. Absence of MRP2 in the BBB led to increased penetration
of phenytoin into the brain and significantly enhanced anticonvulsant activity
compared with rats with intact MRP2 function. Similar results were obtained
when phenytoin was combined with probenecid to inhibit MRP2. A significant
increase of drug penetration into the brain by probenecid has previously been
reported for the major AEDs valproate (Frey
and Löscher, 1978) and carbamazepine
(Potschka et al., 2001) and
has been attributed to inhibition of MRP2 in the BBB
(Löscher and Potschka,
2002). These data and the potentiating effect of probenecid on
phenytoin's anticonvulsant effect in the kindling model suggest novel options
for treatment of refractory epilepsy, such as addition of a MRP2 inhibitor to
current treatment with AEDs. Even though probenecid is not specific for MRP2,
but also inhibits MRP1 and organic anion transports systems, it is often used
as an inhibitor of MRP2 in drug transport studies, especially in tissues, such
as for instance brain capillary endothelial cells, in which MRP1 is not
predominantly expressed (Gerk and Vore,
2002; Löscher and
Potschka, 2002). The use of probenecid as an inhibitor of
MRP2-mediated drug transport in the BBB was substantiated by the present
experiments because similar findings to MRP inhibition by probenecid were
obtained in MRP2-deficient rats. Nevertheless, new, more selective MRP2
inhibitors will hopefully soon become available and should be used instead of
probenecid in experiments on the role of MRP2 in BBB function
(Löscher and Potschka,
2002).
In contrast to phenytoin, phenobarbital's brain distribution or
anticonvulsant activity were not affected by probenecid or lack of MRP2 in the
BBB, indicating that not all AEDs are substrates for this transporter.
However, phenobarbital is a substrate for Pgp
(Potschka et al., 2002) so
that both MRP2 and Pgp act in concert to restrict the brain penetration of
AEDs.
MRP2 is not the only MRP that is located in brain capillary endothelial
cells and is overexpressed in epileptogenic brain tissue of patients with
pharmacoresistant epilepsy (Dombrowski et
al., 2001; Lee et al.,
2001). In addition to the MRP2 gene, the genes encoding for MRP3
and MRP5 were found to be significantly overexpressed in patients with
refractory epilepsy, whereas expression of the MRP1 gene was not significantly
altered (Dombrowski et al.,
2001). Of these MRP genes, the largest overexpression in brain
capillary endothelial cells was seen for the MRP2 gene
(Dombrowski et al., 2001). With
respect to the role of MRPs in BBB function, differences in the cellular
location of MRPs have to be considered. Whereas MRP2 is located in apical cell
membranes, which is the appropriate position for a protective role, other
MRPs, including MRP1, MRP3, and MRP5, are located basolaterally
(Borst et al., 1999), so that
overexpression of the latter MRPs in brain capillary endothelial cells would
not reduce entry of drugs into the brain.
In addition to AEDs, brain pharmacokinetics of drugs comprising the
multidrug resistance phenotype, including anti-cancer drugs, selected
antibiotics, analgesics, antidepressants, antipsychotics, and human
immunodeficiency protease inhibitors
(Fromm, 2000;
Litman et al., 2001;
Taylor, 2002), are likely to
be impacted by the coordinated expression of Pgp and MRPs such as MRP2 in the
BBB. Our results with AEDs suggest that maximizing the brain penetration of
these therapeutic agents may require at least concurrent blockade of both Pgp
and MRP2.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: Pgp, P-glycoprotein; MRP, multidrug resistance protein; BBB, blood-brain barrier; TLE, temporal lobe epilepsy; AED, antiepileptic drug; ANOVA, analysis of variance; GST, generalized seizure threshold; TR–, transport deficient.
Address correspondence to: Dr. W. Löscher, Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany. E-mail: wolfgang.loescher{at}tiho-hannover.de
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