Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein

Baltes, Steffen; Gastens, Alexandra M.; Fedrowitz, Maren; Potschka, Heidrun; Kaever, Volkhard; Löscher, Wolfgang

doi:10.1016/j.neuropharm.2006.07.038

Cited by 212 publications

(170 citation statements)

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“…There are evidences that AEDs are transported by specific proteins. P-glycoprotein (P-gp) is an example of these proteins and the most researched molecule [8,[15][16][17][18]. P-gp is an efflux protein that can be found at the capillary endothelium in the BBB.…”

Section: Genetic Variations In Individuals That May Affect Pharmacokimentioning

confidence: 99%

“…A few studies consistently showed overexpression of P-gp in brain capillary endothelial cells from patients with drug-resistant epilepsy [19,20]. On the other hand, studies on whether AEDs are substrates for P-gp yielded conflicting results [16,[21][22][23]. However, a recent study using concentration equilibrium transport assay has successfully demonstrated that AEDs such as PHT, phenobarbital (PB), lamotrigine (LTG) and levetiracetam are substrates for P-gp [23].…”

Section: Genetic Variations In Individuals That May Affect Pharmacokimentioning

confidence: 99%

“…One study classified patients into poor response group, whereas another study categorized the patients with the same response to AED into good response group [34]. In addition, some previous studies enrolled patients taking AEDs that are not the substrate for P-gp, such as CBZ and valproate [16,21]. The impact of genetic role in the different responses to AED may be less than that of environmental factors such as clinical factors, and the interaction between multiple genetic variations in individuals may be responsible for the different responses to AED.…”

Section: Genetic Variations In Individuals That May Affect Pharmacokimentioning

confidence: 99%

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Genetic variations and response to antiepileptic drug

Kim

2010

E&S

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Despite the state-of-the-art medical treatment with antiepileptic drugs (AED), at least one-third of newly diagnosed epilepsy patients may show poor response to AED. Although the biological mechanism of diverse responses to AED is poorly understood, it is likely that multifactorial factors could be responsible for the different responses. Clinical factors such as etiology of epilepsy and pre-treatment seizure frequency can predict the different responses to AED, whereas the role of genetic variations in individuals contributing to variation in response to AED is still conflicting. The inconsistency in proving the genetic roles in different responses to AED may be partly explained by (1) diversity of the definition of response to AED, (2) heterogeneity of the subjects, and (3) lack of multigenetic approach. While we hypothesize that the genetic variations in individuals may independently contribute to different responses to AED, multigenetic interactions including both the genetic variations of pharmacokinetics and pharmacodynamics may take place.

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Section: Genetic Variations In Individuals That May Affect Pharmacokimentioning

confidence: 99%

Section: Genetic Variations In Individuals That May Affect Pharmacokimentioning

confidence: 99%

Section: Genetic Variations In Individuals That May Affect Pharmacokimentioning

confidence: 99%

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Genetic variations and response to antiepileptic drug

Kim

2010

E&S

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“…7) In case of carbamazepine (one of major AEDs), however, there are contradictions among the papers on the relationship between P-gp function and CBZ disposition. One reports concluded that CBZ is not a substrate for P-gp using mdr1a/1b(Ϫ/Ϫ) knockout mice or P-gp transfected cell lines, 8,9) and the other reports concluded that CBZ is appropriate substrate for P-gp using P-gp transfected cell lines or normal rats with a microdialysis method. 2,7) In addition, study on pharmacoresistance in patients with epilepsy using a radio-labeled P-gp substrate (verapamil) and positron-emission tomography (PET) method showed that regionally enhanced P-gp activity in brain might contribute to drug resistance in some patients with temporal lobe epilepsy.…”

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Evaluation of Carbamazepine Pharmacokinetic Profiles in Mice with Kainic Acid-Induced Acute Seizures

Nishimura

Honda²,

Sugioka³

et al. 2008

Biological & Pharmaceutical Bulletin

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Approximately 30% of epileptic patients do not respond to the usual antiepileptic drugs (AEDs), representing a major problem associated with increased morbidity and mortality. 1) The underlying mechanisms are not completely understood; it has been believed that mechanisms leading to AEDs resistance are most likely complex network phenomena including development of tolerance to antiepileptic drugs' action or alterations in drug targets based on pharmacogenomic factor. 2) Among various transporters, P-glycoprotein (P-gp) has been identified as being important regulators of bioavailabily of drugs, which is located in the endothelial cells of the blood-brain barrier and/or the small intestine, and its outwardly directed active efflux mechanisms from the blood to intestinal lumen or cerebral cell to the blood appear to act as a second line defense mechanism. P-gp, gene product of the multidrug resistance 1 (MDR1 gene ), limiting brain accumulation and intestinal absorption of many lipophilic drugs. [3][4][5][6] Because of lipophilic properties, some AEDs have been established as a substrate of P-gp, and P-gp participates in the regulation of their extracellular brain concentrations. 7) In case of carbamazepine (one of major AEDs), however, there are contradictions among the papers on the relationship between P-gp function and CBZ disposition. One reports concluded that CBZ is not a substrate for P-gp using mdr1a/1b(Ϫ/Ϫ) knockout mice or P-gp transfected cell lines, 8,9) and the other reports concluded that CBZ is appropriate substrate for P-gp using P-gp transfected cell lines or normal rats with a microdialysis method. 2,7) In addition, study on pharmacoresistance in patients with epilepsy using a radio-labeled P-gp substrate (verapamil) and positron-emission tomography (PET) method showed that regionally enhanced P-gp activity in brain might contribute to drug resistance in some patients with temporal lobe epilepsy. 10) These reports indicate that there is complexity to explain the relationship between CBZ therapy and drug resistance through the P-gp function, and it is not known to what extent the P-gp is involved in the transport of CBZ in a living body in epileptic patients. Therefore, it is important that confirmation of Pgp function during seizure in the living organism should be conducted to relief contradictions among those literatures. (Wayne NJ, U.S.A.) and Nikko Chemical Co., Ltd. (Tokyo, Japan). As a primary antibody for P-glycoprotein (P-gp), C219 antibody was purchased from Calbiochemi, Co. (CA, U.S.A.). As a secondary antibody, anti-mouse IgG, immunestar HRP chemiluminescent (ECL) kit was purchased from Bio-Rad Laboratory, Inc. (CA, U.S.A.). All other chemicals were of the highest grade available. MATERIALS AND METHODS MaterialsAnimals All animal experiments were performed in accordance with the Guidelines for Animal Experiments of Kyoto Pharmaceutical University. Male ddy mice (6 weeks old, 28-35 g) were purchased from Japan SLC Inc. (Hamamatsu, Japan), and housed in a temperature and humiditycontrol...

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“…There is significant disagreement in the literature as to whether or not AEDs are all Pgp substrates. Recently, Baltes et al (2007) …”

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2007

Epilepsia

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REFERENCESWhere is the evidence that p-glycoprotein limits brain uptake of antiepileptic drug and contributes to drug resistance in epilepsy? To the Editors:The article by Sisodiya and Goldstein provides an interesting and novel perspective on the current debate over the role of p-glycoprotein (Pgp), or lack thereof, in multidrug resistance in epilepsy. The authors point to a recent report showing that a synonymous single nucleotide polymorphism (i.e., a so-called silent mutation) at the 3435 locus of the multidrug resistant 1 (MDR1 or ABCB1) gene alters Pgp conformation and its interaction with drug substrates and inhibitors, while expression levels of mRNA and protein remain the same (Kimchi-Sarfaty et al., 2007). The synonymous mutation apparently affects the timing of cotranslational folding of Pgp. Based on this postulate, Sisodiya and Goldstein suggest that the functional impact of ABCB1 genotype variation, at least at the 3435 locus, is magnified or becomes apparent when the transcriptional machinery is under stress. They then surmised that severity of "drug-resistance" phenotype (i.e., the demand placed on ABCB1 translation if upregulation of ABCB1 transcription were to occur at the brain capillary endothelium in response to the epileptogenic process or seizure activity) may be an overlooked variable in previous investigations on the possible role of Pgp in rendering resistance to multiple antiepileptic drugs (AEDs). Lack of clear definition and classification of drug-resistance phenotype might have accounted for the discrepancies in the studies of P-pg and drug resistant epilepsy.We agree that differences in the drug-resistance phenotypes between earlier clinical studies may have been a confounding variable; however, a more basic issue is the lack of convincing evidence that (1) AEDs are highaffinity substrates of Pgp and (2) the uptake of the AEDs across the blood-brain barrier (BBB) is dependent on Pgp, especially in cases of apparent drug resistance. There is significant disagreement in the literature as to whether or not AEDs are all Pgp substrates. Recently, Baltes et al. (2007) GRAY MATTERSgathered in animal models to human epilepsies. Overall, the available data in the literature indicate that AEDs are either not substrates or at best very weak substrates of Pgp. One way to illustrate to the relative impact of Pgp on drug uptake into the brain is to compare the reported effects of selective Pgp inhibitors (verapamil, PSC-833) on the brain-to-plasma or microdialysate-to-plasma ratio for AEDs and classic Pgp substrates, namely, vincristine, cyclosporine, and digoxin. For vincristine, Pgp inhibition resulted in a 9-fold increase in brain uptake (Drion et al., 1996). In comparison, Pgp inhibition only increased phenytoin, carbamazepine, phenobarbital, lamotrigine, and felbamate, 0.5-to 1.1-fold over baseline Potschka et al., , 2002. In the ABCB1a knockout mouse model, vinblastine, cyclosporine, and digoxin brain uptake increased 20-to 50-fold (Schinkel et al., 1994;Schinkel et al., 1995). In compari...

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Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein

Cited by 212 publications

References 42 publications

Genetic variations and response to antiepileptic drug

Genetic variations and response to antiepileptic drug

Evaluation of Carbamazepine Pharmacokinetic Profiles in Mice with Kainic Acid-Induced Acute Seizures

Next Month in Epilepsia

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