期刊
PHARMACOGENETICS AND GENOMICS
卷 21, 期 10, 页码 624-630出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FPC.0b013e3283498131
关键词
blood-brain barrier; drug transport; multi-drug-resistance protein 2; pharmacotherapy resistance
Background Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters, in particular ABCB1. Recently, we found a significant association of ABCC2 -24C > T with nonresponse, primarily in the context of generalized epilepsy. Moreover, ABCC2 1249G > A was reported to alter transmembranal carbamazepine transport. Therefore, we aimed to confirm the association of ABCC2 variants with pharmacotherapy-resistance in Caucasians mainly affected by partial epilepsy. Patients and methods A total of 208 patients (114 male; age: 11.3 +/- 5.9 years) were genotyped for three putatively functionally relevant polymorphisms of ABCC2 (-24C > T, 1249G > A, 3972C > T). Genotype and haplotype frequencies were compared between responders and nonresponders to first-line antiepileptic treatment. Results Carriers of the ABCC2 1249G > A variant (417V>I) were more frequent among responders [odds ratio (OR)=2.68 (1.25-5.78); P=0.010]. This association remained significant after adjusting for age, sex and seizure type, [OR=2.88 (1.23-6.73); P=0.015]. The impact of 1249G > A was more pronounced among 64 patients receiving carbamazepine or oxcarbazepine (P=0.005), but nonsignificant in patients receiving other anticonvulsants. ABCC2 -24C > T and 3972C > T showed lack of association to therapy response. Haplotype analyses revealed that haplotype H2 containing solely the 1249A variant allele was more frequent in the responder group [OR=2.98 (1.38-6.44); P=0.004]. Discussion These data argue for a greater probability of antiepileptic drug response among carriers of the ABCC2 1249A variant that is associated with reduced carbamazepine transport. Although we could not confirm an impact of ABCC2 -24C > T, these results suggest that ABCC2 genotype may also modulate the response to anticonvulsants besides the extensively studied ABCB1 (P-glycoprotein). Pharmacogenetics and Genomics 21: 624-630 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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