Potential role of multidrug resistant proteins in refractory epilepsy and antiepileptic drugs interactions

Lazarowski, Alberto; Czornyj, Liliana

doi:10.1515/dmdi.2011.006

Cited by 43 publications

(31 citation statements)

References 36 publications

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“…Our results might indicate another potential mechanism, namely reduced degree in calcineurin inhibitors-induced (CNI) toxicity due to the faster elimination of CNI into the proximal tubular lumen by cysteamine mediated P-gp stimulation. Whether the observed small increase in P-gp activity is clinically relevant needs to be determined, but as shown for single nucleotide polymorphisms in MDR1 leading to gain in function of P-gp, as seen for instance for MDR1 polymorphisms in epilepsia treatment [13], this might have an impact for pharmacotherapy. The increase in P-gp activity is interesting and possibly related to multiple binding sites on P-gp that are allosterically linked [14,15].…”

Section: Resultsmentioning

confidence: 99%

Role of P-Glycoprotein Expression and Function in Cystinotic Renal Proximal Tubular Cells

et al. 2011

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P-glycoprotein (P-gp) is an ATP-dependent transporter localized at the apical membrane of the kidney proximal tubules, which plays a role in the efflux of cationic and amphipathic endogenous waste products and xenobiotics, such as drugs, into urine. Studies in mice deficient in P-gp showed generalized proximal tubular dysfunction similar to the phenotype of patients with cystinosis, an autosomal recessive disorder caused by mutations in the lysosomal cystine transporter cystinosin. Renal disease in cystinosis is characterized by generalized dysfunction of the apical proximal tubular influx transporters (so-called renal Fanconi syndrome) developing during infancy and gradually progressing towards end-stage renal disease before the 10th birthday in the majority of patients that are not treated with the cystine-depleting drug cysteamine. Here, we investigated whether the proximal tubular efflux transporter P-gp is affected in cystinosis and whether this might contribute to the development of renal Fanconi syndrome. We used conditionally immortalized (ci) proximal tubular epithelial cells (ciPTEC) derived from cystinotic patients and healthy volunteers. P-gp-mediated transport was measured by using the P-gp substrate calcein-AM in the presence and absence of the P-gp-inhibitor PSC833. P-gp activity was normal in cystinotic cells as compared to controls. Additionally, the effect of cysteamine on P-gp transport activity and phosphate uptake was determined; demonstrating increased P-gp activity in cystinotic cells, and further decrease of proximal tubular phosphate uptake. This observation is compatible with the persistence of renal Fanconi syndrome in vivo under cysteamine therapy. In summary, P-gp expression and activity are normal in cystinotic ciPTEC, indicating that P-gp dysfunction is not involved in the pathogenesis of cystinosis.

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Section: Resultsmentioning

confidence: 99%

Role of P-Glycoprotein Expression and Function in Cystinotic Renal Proximal Tubular Cells

et al. 2011

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“…Refractory epilepsy is a common neurologic disease that accounts for approximately one-third of epileptic patients with resistance to single or multiple drugs used for antiepileptic treatment [1,2] . Clinical studies have shown that if the first antiepileptic drug (AED) prescribed was ineffective, switching to another AED or to a combination of AEDs yielded similar negative results.…”

Section: Introductionmentioning

confidence: 99%

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

et al. 2013

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Aim: To investigate whether multidrug resistance-associated protein 1 (MRP1) was responsible for drug resistence in refractory epilepsy in amygdale kindling rats. Methods: Rat amygdale kindling was used as a model of refractory epilepsy. The expression of MRP1 mRNA and protein in the brains was examined using RT-PCR and Western blot. MRP1-positive cells in the cortex and hippocampus were studied with immunohistochemical staining. The rats were intraperitoneally injected with phenytoin (50 mg/kg) or carbamazepine (20 mg/kg), and their concentrations in the cortical extracellular fluid were measured using microdialysis and HPLC. Probenecid, a MRP1 inhibitor (40 mmol/L, 50 μL) was administered through an inflow tube into the cortex 30 min before injection of the antiepileptic drugs. Results: The expression of MRP1 mRNA and protein was significantly up-regulated in the cortex and hippocampus in amygdale kindling rats compared with the control group. Furthermore, the number of MRP1-positive cells in the cortex and hippocampus was also significantly increased in amygdale kindling rats. Microdialysis studies showed that the concentrations of phenytoin and carbamazepine in the cortical extracellular fluid were significantly decreased in amygdale kindling rats. Pre-administration of probenecid could restore the concentrations back to their control levels. Conclusion: Up-regulation of MRP1 is responsible for the resistance of brain cells to antiepileptic drugs in the amygdale kindling rats.

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“…Two well-known hypotheses have emerged to explain at least part of the biological mechanism underlying drug resistance: the target hypothesis and the transporter hypotheses [71]. The target hypothesis suggests that alterations in specific drug targets results in reduction of AED sensitivity [72] and it proposes that increased expression of multidrug transporter proteins at the blood-brain barrier leads to decreased bioavailability and limited brain access of AEDs that may result in drug resistance [73].…”

Section: Pharmacogenetics Of Carbamazepine Transporters and Targetsmentioning

confidence: 99%

Pharmacogenetic potential biomarkers for carbamazepine adverse drug reactions and clinical response

Monroy-Jaramillo

Fricke-Galindo

Vázquez

et al. 2014

Drug Metabolism and Drug Interactions

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Carbamazepine (CBZ) is a first-line widely used anticonvulsant. It has a narrow therapeutic index and exhibits considerable interindividual and interethnic variability in clinical efficacy and adverse drug reactions including potentially life-threatening hypersensitivity reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The most important pharmacogenetic finding is related to the association of CBZ-induced hypersensitivity with human leukocyte antigens (HLA class I and II alleles). Moreover, genotyping for HLA-B*15:02 allele is required prior to initiating CBZ in Asians and Asian ancestry patients, demonstrating the usefulness of biomarkers to avoid adverse drug reactions. On the other hand, in order to explain the differences in the clinical response to CBZ, genetic polymorphisms in phase I (CYP3A4, CYP3A5 and EPHX1) and phase II (UGT2B7) metabolising enzymes have been assessed; additionally, the influence of transporters (ABCB1 and ABCC2), receptors (PXR) and other drug targets (voltage- gated Na+ channels) in CBZ clinical response has been evaluated. To date, these studies are controversial and require further investigations to clarify the functional role of these polymorphisms as potential biomarkers in regard to CBZ therapy.

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Potential role of multidrug resistant proteins in refractory epilepsy and antiepileptic drugs interactions

Cited by 43 publications

References 36 publications

Role of P-Glycoprotein Expression and Function in Cystinotic Renal Proximal Tubular Cells

Role of P-Glycoprotein Expression and Function in Cystinotic Renal Proximal Tubular Cells

Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

Pharmacogenetic potential biomarkers for carbamazepine adverse drug reactions and clinical response

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