The Antiepileptic Drug Topiramate is a Substrate for Human P-glycoprotein but Not Multidrug Resistance Proteins

Luna-Tortós, Carlos; Rambeck, B.; Jürgens, Uwe; Löscher, Wolfgang

doi:10.1007/s11095-009-9961-8

Cited by 45 publications

(16 citation statements)

References 32 publications

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“…When 1,25(OH) 2 D 3 is used in combination with anticancer agents such as paclitaxel, a known P-gp substrate, to treat cancer (Masuda and Jones, 2006), lower therapeutic effects may result in the brain. P-gp substrates targeting the brain include the antiretrovirals such as atazanavir, ritonavir, and jpet.aspetjournals.org saquinavir for HIV treatment, antipsychotics such as risperidone (Kim, 2002;Zastre et al, 2009), antiepileptic drugs such as topiramate (Luna-Tortós et al, 2009), or central nervous system drugs such as morphine (Groenendaal et al, 2007), and all of these probably will be affected. On the other hand, increased P-gp activity may decrease brain concentration of a drug such as oseltamivir (Tamiflu), a drug used for influenza treatment, which is a P-gp substrate (Morimoto et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

1α,25-Dihydroxyvitamin D₃Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo

Chow

Durk²,

Cummins³

et al. 2011

J Pharmacol Exp Ther

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Secondary farnesoid X receptor (FXR) effects, in addition to vitamin D receptor (VDR) effects, were observed in the rat liver after treatment with 1␣,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the natural ligand of VDR, caused by increased bile acid absorption as a consequence of apical sodium-dependent bile acid transporter induction. To investigate whether the increased multidrug resistance protein 1 (Mdr1)/P-glycoprotein (P-gp) expression in the rat liver and kidney was caused by the VDR and not the FXR, we examined changes in Mdr1/P-gp expression in fxr(ϩ/ϩ) and fxr(Ϫ/Ϫ) mice after intraperitoneal dosing of vehicle versus 1,25(OH) 2 D 3 (0 or 2.5 g/kg every other day for 8 days). Renal and brain levels of Mdr1 mRNA and P-gp protein were significantly increased in both fxr(ϩ/ϩ) and fxr(Ϫ/Ϫ) mice treated with 1,25(OH) 2 D 3 , confirming that Mdr1/ P-gp induction occurred independently of the FXR. Increased P-gp function was evident in 1,25(OH) 2 D 3 -treated fxr(ϩ/ϩ) mice given intravenous bolus doses of the P-gp probe, [3 H]digoxin (0.1 mg/kg). Decreased blood (24%) and brain (29%) exposure, estimated as reduced areas under the curve, caused by increased renal (74%) and total body (34%) clearances of digoxin, were observed in treated mice. These events were predicted by physiologically based pharmacokinetic modeling that showed increased renal secretory intrinsic clearance (3.45-fold) and brain efflux intrinsic clearance (1.47-fold) in the 1,25(OH) 2 D 3 -treated mouse, trends that correlated well with increases in P-gp protein expression in tissues. The clearance changes were less apparent because of the high degree of renal reabsorption of digoxin. The observations suggest an important role of the VDR in the regulation of P-gp in the renal and brain disposition of P-gp substrates.

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Section: Discussionmentioning

confidence: 99%

1α,25-Dihydroxyvitamin D₃Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo

Chow

Durk²,

Cummins³

et al. 2011

J Pharmacol Exp Ther

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“…Luna-Tortós et al (110) pointed out that conventional bidirectional transport assays may not be suitable to identify ASDs as P-gp substrates due to the highly permeable nature of most ASDs. Using a modified transport assay (concentration equilibrium transport assay; CETA) which allows evaluating active transport separately from passive permeability, Luna-Tortós et al detected P-gp transport of phenytoin, phenobarbital, lamotrigine, levetiracetam, and topiramate, but not carbamazepine in MDR1-transfected LLC-PK1 cells (110, 111). Zhang et al (101) used both the cell monolayer bidirectional assay and CETA in MDR1-transfected MDCKII and LLC-PK1 cells to test if phenytoin, phenobarbital, or ethosuximide were transported by P-gp.…”

Section: Potential Mechanisms Of Asd Resistancementioning

confidence: 99%

“…Using CETA in MDCKII kidney cells transfected with human MRP1, MRP2, or MRP5, Luna-Tortós et al reported that none of the ASDs tested (topiramate, valproate, carbamazepine, phenytoin, levetiracetam, lamotrigine, and phenobarbital) was transported by any of those MRPs (111, 112). In vivo studies may be needed to confirm the findings from in vitro experiments, but few clinical studies have focused on studying the relationship between ASDs and MRPs.…”

Section: Potential Mechanisms Of Asd Resistancementioning

confidence: 99%

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

2017

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Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.

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“…In addition, administration of TPM in patients already taking phenytoin twice a day, a 25% rise in the concentrations of phenytoin were found and may require a downward adjustment of phenytoin dosage (47). Besides in patients with pharmacoresistant epilepsy, Luna-Tortos et al (2009) (48) provided evidence that brain levels of topiramate may be affected by overexpression of P-glycoprotein. Enhanced elimination of TPM was also observed during pregnancy.…”

Section: Antiepileptic Drugs (Structures See Figure 2)mentioning

confidence: 99%

An overview on antiepileptic drugs

2012

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Epilepsy is the most common chronic neurological disorder of the brain. For several decades different kinds of medications have been used to treat epilepsy. Even though many surgical advances has been made and implemented, medications remain the basis of treatment. The search for noble antiepileptic drugs (AEDs) with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. Additionally, drug resistance is an important clinical problem in epilepsy and is associated with an increased risk of morbidity and mortality. This review intends to present a comprehensive overview on AED in particular along with discussion on some aspects of associated drug resistance and combination therapy.

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The Antiepileptic Drug Topiramate is a Substrate for Human P-glycoprotein but Not Multidrug Resistance Proteins

Abstract: Thus, these data indicate that brain levels of topiramate may be affected by overexpression of Pgp as determined in patients with intractable epilepsy.

Cited by 45 publications

References 32 publications

1α,25-Dihydroxyvitamin D₃Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo

1α,25-Dihydroxyvitamin D₃Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

An overview on antiepileptic drugs

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The Antiepileptic Drug Topiramate is a Substrate for Human P-glycoprotein but Not Multidrug Resistance Proteins

Abstract: Thus, these data indicate that brain levels of topiramate may be affected by overexpression of Pgp as determined in patients with intractable epilepsy.

Cited by 45 publications

References 32 publications

1α,25-Dihydroxyvitamin D3Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo

1α,25-Dihydroxyvitamin D3Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

An overview on antiepileptic drugs

Contact Info

Product

Resources

About

1α,25-Dihydroxyvitamin D₃Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo

1α,25-Dihydroxyvitamin D₃Up-Regulates P-Glycoprotein via the Vitamin D Receptor and Not Farnesoid X Receptor in Bothfxr(−/−) andfxr(+/+) Mice and Increased Renal and Brain Efflux of Digoxin in Mice In Vivo