Polymorphism of the MDR1/ABCB1 C3435T drug‐transporter and resistance to anticonvulsant drugs: A meta‐analysis

Garcia‐Bournissen, Facundo; Moretti, Myla E; Juurlink, David N.; Koren, Gideon; Walker, M.J. Katharine; Finkelstein, Yaron

doi:10.1111/j.1528-1167.2008.01858.x

Cited by 100 publications

(83 citation statements)

References 27 publications

(79 reference statements)

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“…39 Further, it has been suggested that drug refractory epilepsy may be related to gain-of-function ABCB1 SNPs. [40][41][42][43][44] In experimental models, ABCB1, predominantly expressed in brain microvessels at baseline, 45 is reduced 2 months after controlled cortical impact in juvenile rats. 46 Our data did not reveal differences between relative protein levels of ABCB1 in TBI versus controls; however, this could be because of the limited sample size and/or the fact that the average time from injury to biopsy was 37 h.…”

Section: Abcc1 and Abcb1 In Human Brain After Severe Tbimentioning

confidence: 99%

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Willyerd

Empey

Philbrick

et al. 2016

Journal of Neurotrauma

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Adenosine triphosphate-binding cassette (ABC) transport proteins ABCC1 and ABCB1 (also known as multidrug resistance-associated protein 1 and p-glycoprotein, respectively), are key membrane efflux transporters of drugs and endogenous substrates, including in the brain. The impact of traumatic brain injury (TBI) on ABCC1 and ABCB1 expression in humans is unknown. We hypothesized that ABCC1 and ABCB1 expression would be altered in brain tissue from patients acutely after severe TBI. Archived TBI samples (n = 10) from our Brain Trauma Research Center and control samples (n = 7) from our Alzheimer Disease Research Center were obtained under Institutional Review Board approval. Protein was extracted from fresh frozen cortical brain tissue for Western blot analysis and sections were obtained from fixed cortical tissue for immunohistochemistry. Relative abundance of ABCC1 was increased in samples from TBI versus controls (2.8 -2.5 fold; p = 0.005). ABCC1 immunohistochemistry was consistent with Western blot data, with increased immunoreactivity in cerebral blood vessel walls, as well as cells with the morphological appearance of neurons and glia in TBI versus controls. Relative abundance of ABCB1 was similar between TBI and controls ( p = 0.76), and ABCB1 immunoreactivity was primarily associated with cerebral blood vessels in both groups. These human data show that TBI increases ABCC1 expression in the brain, consistent with possible implications for both patients receiving pharmacological inhibitors and/or substrates of ABCC1 after TBI.

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Section: Abcc1 and Abcb1 In Human Brain After Severe Tbimentioning

confidence: 99%

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Willyerd

Empey

Philbrick

et al. 2016

Journal of Neurotrauma

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“…Several recent meta analyses of studies investigating the c.3435C>T polymorphism are listed in table 3. Digoxin pharmacokinetics were not affected by c.3435C>T [98] and the response to anticonvulsant drugs exhibited also no association with this polymorphism [99,100]. In contrast, the effects on cyclosporine pharmacokinetics are more complex: Overall, there was no effect of the c.3435C>T ABCB1 polymorphism on the pharmacokinetic parameters, although the total cyclosporine bioavailability (AUC 0-12 ) was slightly reduced (table 3) [101].…”

Section: Mdr1 (Abcb1)mentioning

confidence: 87%

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Stieger

Meier

2011

Pharmacogenomics

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This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.

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“…Epilepsy patients with the CC genotype had lower levels of phenobarbital in the CSF and exhibited higher seizure activity [72]. The first study, in 2003, suggested that the 3435C > T polymorphism may explain resistance to AED therapy in epilepsy [73], but several other association studies, as well as meta-analyses, have clearly demonstrated that the impact of ABCB1 genetics on the pharmacoresistance of AEDs is inconsistent [62,74,75]. However, the concept that Pgp expression and function may be directly associated with pharmacoresistant temporal lobe epilepsy in patients has been very recently corroborated by a highly attractive approach investigating Pgp activity in patients with epilepsy using positron emission tomography technology [76].…”

Section: Role Of Drug Distribution For Pharmacoresponsementioning

confidence: 99%

Genetic Biomarkers in Epilepsy

et al. 2014

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The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of interest in medicine. The concept of individualized therapy is becoming increasingly important in the treatment of patients with epilepsy, as predictive markers for disease prognosis and treatment outcome are still limited. Currently, the clinical decision process for selection of an antiepileptic drug (AED) is predominately based on the patient's epileptic syndrome and side effect profiles of the AEDs, but not on effectiveness data. Although standard dosages of AEDs are used, supplemented, in part, by therapeutic monitoring, the response of an individual patient to a specific AED is generally unpredictable, and the standard care of patients in antiepileptic treatment is more or less based on trial and error. Therefore, there is an urgent need for valid predictive biomarkers to guide patient-tailored individualized treatment strategies in epilepsy, a research area that is still in its infancy. This review focuses on genomic factors as part of an individual concept for AED therapy summarizing examples that influence the prognosis of the disease and the response to AEDs, including side effects.

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Polymorphism of the MDR1/ABCB1 C3435T drug‐transporter and resistance to anticonvulsant drugs: A meta‐analysis

Cited by 100 publications

References 27 publications

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Genetic Biomarkers in Epilepsy

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