Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug transporters are increasingly recognized to be important to drug disposition and response. P-glycoprotein, the encoded product of the human MDR1 (ABCB1) gene, is of particular clinical relevance in that this transporter has broad substrate specificity, including a variety of structurally divergent drugs in clinical use today. Moreover, expression of this efflux transporter in certain tissue compartments such as the gastrointestinal tract and brain capillary endothelial cells limits oral absorption and central nervous system entry of many drugs. Recently, a number of single-nucleotide polymorphisms (SNPs) in MDR1 have been identified. An increasing number of studies have also implicated certain commonly occurring SNPs in MDR1 in problems including altered drug levels and host susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and CD4 cell recovery during human immunodeficiency virus therapy. However, in many such cases, the reported effects of MDR1 SNPs have been inconsistent and, in some cases, conflicting. In this review SNPs in MDR1 in relation to population frequencies, drug levels, and phenotypes are outlined. In addition, issues relating to MDR1 haplotypes, environmental factors, and study design, as potential confounding factors of the observed MDR1 polymorphism effect in vivo, are also discussed.
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PMID:Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. 1474 89

Increased expression of the multidrug transporter P-glycoprotein (Pgp; ABCB1) has previously been found in epileptogenic brain tissue from patients with pharmacoresistant temporal lobe epilepsy (TLE) as well as in the hippocampus and other limbic brain regions in the rat kainate model of TLE. Approaches to the quantification of Pgp expression have mainly been based on subjective visual estimation of the level of Pgp immunoreactivity in brain sections. In the present study, computer-assisted image analysis based on optical density (OD) measurements was used to examine immunohistochemical expression of Pgp in the kindling model of TLE. Sections from kainate-treated rats were used for comparison. Using diaminobenzidine as chromogen, Pgp was exclusively located in brain capillary endothelial cells, which was confirmed by double-labeling with an antibody against the endothelial glucose transporter (GLUT-1). After kainate-induced seizures, the intensity of endothelial Pgp staining significantly increased by 70-80% in the dentate gyrus. A significant, albeit less marked increase in Pgp expression in this area was also seen after amygdala-kindled seizures. Furthermore, Pgp was upregulated after kindling in the hilus of the dentate gyrus, the CA1 and CA3 sectors of the hippocampus, and the piriform and cerebral cortex. In kindled rats, most Pgp alterations occurred ipsilateral to the electrode in the basolateral amygdala. The data demonstrate that computer-assisted image analysis using OD is an accurate and rapid method to determine the relative amount of Pgp protein in brain sections and the effects of seizures on this multidrug transporter. The fact that Pgp overexpression in brain capillary endothelial cells occurs in two established models of difficult-to-treat TLE substantiates the notion that seizure-induced upregulation of Pgp contributes to multidrug resistance (MDR) in epilepsy.
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PMID:Increased expression of the multidrug transporter P-glycoprotein in limbic brain regions after amygdala-kindled seizures in rats. 1506 76

Overexpression of multidrug efflux transporters such as P-glycoprotein (Pgp; ABCB1) or multidrug resistance proteins (MRPs; ABCC) in the blood-brain barrier has recently been suggested to explain, at least in part, pharmacoresistance in epilepsy, which affects about 30% of all patients with this common brain disorder. The novel antiepileptic drug (AED) levetiracetam (LEV) is an effective and well tolerated drug in many patients with otherwise AED-refractory epilepsy. One explanation for the favorable efficacy of LEV in pharmacoresistant patients would be that LEV is not a substrate for Pgp or MRPs in the BBB. In the present study, we used in vivo microdialysis in rats to study whether the concentration of LEV in the extracellular fluid of the cerebral cortex can be modulated by inhibition of Pgp or MRPs, using the Pgp inhibitor verapamil and the MRP1/2 inhibitor probenecid. Local perfusion with verapamil or probenecid via the microdialysis probe did not increase the extracellular brain concentration of LEV, which is in contrast to various other AEDs which have been studied previously by the same experimental protocol in this model. The data indicate that brain uptake of LEV is not affected by Pgp or MRP1/2 which may be an important reason for its antiepileptic efficacy in patients whose seizures are poorly controlled by other AEDs.
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PMID:Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats. 1512 Jul 40

Drug transporters significantly influence drug pharmacokinetics and pharmacodynamics. P-glycoprotein (P-gp), the product of the MDR1 (ABCB1) gene, is among the most well-characterized drug transporters, particularly in veterinary medicine. A number of clinically relevant, structurally and functionally unrelated drugs are substrates for P-gp. P-gp is expressed by a variety of normal tissues including the intestines, renal tubular cells, brain capillary endothelial cells, biliary canalicular cells, and others, where it functions to actively extrude substrate drugs. In this capacity, P-gp limits oral absorption and central nervous system entry of many substrate drugs. A number of MDR1 polymorphisms have been described in human patients, some of which result in altered drug pharmacokinetics and susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and others. An MDR1 polymorphism in herding breed dogs, including collies and Australian shepherds, has been demonstrated to be the cause of ivermectin sensitivity in these breeds. Recent evidence suggests that this polymorphism, a 4-bp deletion mutation, results in increased susceptibility to the toxicity of several drugs in addition to ivermectin. Furthermore, data in rodent models suggest that P-gp may play an important role in regulating the hypothalamic-pituitary-adrenal axis.
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PMID:Therapeutic implications of the MDR-1 gene. 1550 May 62

The pathogenesis underlying pharmacoresistance in epilepsy is unclear. One of the candidate mechanisms that has attracted growing interest is the limitation of antiepileptic drug (AED) access to the seizure focus by a range of efflux transporters, the prototype of which is P-glycoprotein (P-gp). P-gp is encoded by the multidrug resistance (MDR1 or ABCB1) gene. Predominantly expressed in organs with excretory functions and at blood-tissue barriers, P-gp is thought to act as a physiologic defense by extruding xenobiotics from mammalian cells and affording protection of sensitive organs. The high level of P-gp in the cerebrovascular endothelium is believed to contribute to the functionality of the blood-brain barrier. Overexpression of P-gp causes multidrug resistance in certain cancers. It has been hypothesized that overexpression of P-gp and other efflux transporters in the cerebrovascular endothelium, in the region of the epileptic focus, also may lead to drug resistance in epilepsy. This hypothesis is supported by the findings of elevated expression of efflux transporters in epileptic foci in patients with drug-resistant epilepsy, induction of expression by seizures in animal models, and experimental evidence that some commonly used AEDs are substrates. Conflicting reports suggest a possible association between variants of the MDR1 gene and medical intractability in epilepsy. Further studies to delineate the exact role, if any, of P-gp and other efflux transporters in drug-resistant epilepsy are warranted.
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PMID:Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. 1567 3

Medical intractability, i.e. the absence of any response to anti-epileptic drug (AED) therapy, is an unresolved problem in many patients with epilepsy. Mechanisms of intractability are not well understood, but may include alterations of pharmacological targets and poor penetration of AEDs into the brain because of increased expression of multiple drug-resistance proteins, such as P-glycoprotein (Pgp; ABCB1), capable of active brain extrusion of various drugs, including AEDs. Increased expression of Pgp has been reported in brain tissue of patients with refractory epilepsy, but there is a lack of adequate controls, i.e. brain tissue from patients with drug-responsive epilepsy. In the present study, we used a rat model of temporal lobe epilepsy to examine whether AED responders differ from non-responders in their expression of Pgp in the brain. In this model, spontaneous recurrent seizures develop after status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video-EEG monitoring before, during and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders (n = 7) and non-responders (n = 4). Pgp expression was studied by immunohistochemistry and showed striking overexpression in non-responders compared with responders in limbic brain regions, including the hippocampus. The Pgp overexpression was confined to brain capillary endothelial cells which form the blood-brain barrier. The present data are the first to demonstrate that rats with drug-resistant spontaneous seizures differ from rats with drug-responsive seizures in their Pgp expression in the brain, thereby substantiating the multidrug transporter hypothesis of intractable epilepsy.
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PMID:Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. 1571 4

Multidrug resistance protein, also referred as P-glycoprotein (P-gp, MDR1; ABCB1) and multidrug resistance-associated protein (MRP) 1 (ABCC1) and 2 (ABCC2) are, thus far, candidates to cause antiepileptic drug (AED) resistance epilepsy. In this study, we investigated P-gp, MRP1 and MRP2 expression, localization and functional activity on cryosections and isolated human brain-derived microvascular endothelial cells (HBMEC) from epileptic patients (HBMEC-EPI) with hippocampal sclerosis (HS), as compared with HBMEC isolated from normal brain cortex (HBMEC-CTR). We examined the expression and distribution of three transporters, P-gp, MRP1 and MRP2 on two major parts of the resected tissue, the hippocampus and the parahippocampal gyrus (Gph). P-gp showed diffuse expression not only in endothelium but also by parenchymal cells in both the hippocampus and the Gph. MRP1 labeling was observed in parenchymal cells in the Gph. By contrast, MRP2 was mainly found in endothelium of the hippocampus. P-gp and MRP1 expression in the Gph was relatively high in the patient with long-term seizure history. Quantitative RT-PCR analysis of HBMEC revealed that MDR1, MRP1 as well as MRP5 (ABCC5) and MRP6 (ABCC6) were overexpressed in HBMEC-EPI at the mRNA level. HBMEC from both normal and epilepsy groups displayed protein expression of P-gp, whereas MRP1 and MRP2 were seen only in HBMEC-EPI. Accordingly, it is of particular interest that MRP functional activities were observed in HBMEC-EPI, but not in HBMEC-CTR. Our results suggest that complex MDR expression changes not only in the hippocampus but in the Gph may play a role in AED pharmacoresistance in intractable epilepsy patients with mesial temporal lobe epilepsy (MTLE) by altering the permeability of AEDs across the blood-brain barrier (BBB).
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PMID:Distribution and functional activity of P-glycoprotein and multidrug resistance-associated proteins in human brain microvascular endothelial cells in hippocampal sclerosis. 1636 Oct 82

Controversy has surrounded the reported association of the single nucleotide polymorphism (SNP) C3435T of the ATP-binding cassette subfamily B member 1 (ABCB1, MDR1) gene, with refractory epilepsy. Here we examine this question by: (1) attempting to replicate the original association, (2) assessing the association of other variants in high linkage disequilibrium (LD) with C3435T, and (3) evaluating and comparing our findings with other published studies. We defined drug-responsiveness as seizure freedom or a 50% or more reduction in seizure frequency in the preceding year. Drug resistance was defined as a less than 50% reduction in seizure frequency in the preceding year. We used a combination of map-based (tagging SNPs) and direct sequence-based methods allowing a comprehensive assessment of variation across the associated interval. Genotypic data on 8 SNPs was collected on 440 patients, of whom 242 were drug-responsive and 198 were drug-resistant. We were unable to observe the original association of drug-resistant epilepsy with C3435T, nor any association with other functional variants at SNP or haplotype level in the ABCB1 gene. Evaluation of other attempted replication studies suggest that if the original C3435T association is indeed real, it would appear highly sensitive to the phenotype used. Alternatively, the discrepant results of this and other association attempts may be indicative of the original report of the CC genotype at C3435T in ABCB1 being a false positive finding. Variability in phenotypic descriptions in genetic association studies may partly explain the inconsistency of attempted replications.
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PMID:The controversial association of ABCB1 polymorphisms in refractory epilepsy: an analysis of multiple SNPs in an Irish population. 1712 69

One of the major neurobiological mechanisms proposed in drug resistant epilepsy is removal of anti-epileptic drugs (AEDs) from the epileptogenic tissue through excessive expression of multi-drug efflux transporters such as P-glycoprotein (P-gp). P-gp, the encoded product of the human multi-drug resistance-1 (MDR-1; ABCB1) gene, is of particular clinical relevance in the emergence of multi-drug resistance (MDR), which may play an important role in preventing treatment response of some tumors and infectious diseases to chemotherapeutic agents and antibiotics. It has been shown that MDR-1 is over-expressed in brain tissue (hippocampal neurons) in patients with refractory temporal lobe epilepsy. For direct evidence that drug transporters such as P-gp are responsible for drug resistance, an experiment can be conducted to determine whether seizure control is improved when P-gp inhibitors are administered in addition to existing AEDs in patients with medically refractory epilepsy. In comparison with first and second-generation of P-gp inhibitors, third-generation inhibitors such as pyronaridine (PND) have advantages, such as higher potency and specificity for P-gp, lack of non-specific cytotoxicity, relatively long duration of action with reversibility, and good oral bioavailability. We suggest that a pilot study be conducted to determine whether adding of PND to existing AEDs decreases seizure frequency in patients with drug resistant epilepsy, and should this show promise, that a double-blind randomized controlled trial be designed to test the efficacy of PND.
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PMID:Potentiation of anti-epileptic drugs effectiveness by pyronaridine in refractory epilepsy. 1736 47

There is accumulating evidence to suggest that overexpression of efflux drug transporters at the blood-brain barrier, by reducing antiepileptic drug (AED) accumulation in the seizure foci, contributes to drug resistance in epilepsy. P-glycoprotein, encoded by the ABCB1 gene, is the most studied drug transporter. There are conflicting data as to whether the CC genotype of the ABCB1 3435C>T polymorphism is associated with drug resistance in Caucasian patients with epilepsy. We investigated this association in ethnic Chinese. ABCB1 3435C>T was genotyped in 746 Han Chinese patients with epilepsy and 179 controls. Patients with drug-resistant epilepsy were more likely to have the TT genotype compared with those with drug-responsive epilepsy (16.7% vs 7.4%, odds ratio=2.5, 95% confidence interval=1.4-4.6, P=0.0009). Our results contrast with those of studies of Caucasians, and highlight the complexity of the possible role of this polymorphism in AED response in different ethnic populations.
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PMID:Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese. 1752 63


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