title: A comprehensive functional and clinical analysis of ABCC2 and its impact on treatment response to carbamazepine.
abstract: At the blood-brain barrier, overexpression of the drug efflux transporter ABCC2 (also known as MRP2) has been proposed as a mechanism for impaired carbamazepine (CBZ) treatment response in epilepsy. However, investigation of the impact of ABCC2 polymorphisms on CBZ treatment efficacy has produced conflicting and inconclusive results. A series of in vitro cell efflux and plasma membrane vesicle uptake assays were undertaken to investigate whether CBZ was an ABCC2 substrate. In addition, the effect of three common ABCC2 polymorphisms, -24C>T, c.1249G>A and c.3972C>T, on the efficacy of CBZ in epilepsy (assessed using the clinical end points time to first seizure and time to 12-month remission from the SANAD (Standard and New Antiepileptic Drugs) trial) was determined. CBZ was found not to be a substrate for human ABCC2 in vitro. Clinically, no significant association was observed for the ABCC2 genetic variants and CBZ treatment outcomes. This comprehensive analysis does not support a role for ABCC2 in CBZ treatment efficacy.
authors.affiliation: Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: S
authors.initials: S
authors.lastname: Rädisch
authors.affiliation: Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: D
authors.initials: D
authors.lastname: Dickens
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Lang
authors.affiliation: Department of Biostatistics and Department of Clinical Infection, Microbiology and Immunology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: L
authors.initials: L
authors.lastname: Bonnett
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Arlanov
authors.affiliation: Department of Medicine, Division of Brain Science, Imperial College London, London, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Johnson
authors.affiliation: 1] Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany [2] Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Marson
authors.affiliation: Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000328:Adult; D002220:Carbamazepine / Q000627:therapeutic use*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D002220:Carbamazepine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human