Abstracts

Rationale: Multidrug resistance-associated protein 2 (MRP2) transports many anti-epileptic drugs (AEDs) and is upregulated in the brain tissues of epilepsy patients. In this study, associations between MRP2 polymorphisms and the individual drug responses of AEDs, especially carbamazepine, were analyzed using an integrated population genetic and molecular functional approach.Methods: Eleven single nucleotide polymorphisms in the MRP2 gene were analyzed in 146 epilepsy patients. Patients were divided into two groups, those who experienced the adverse drug reactions (ADR) of central nervous system (n=47) and those who did not (n=99).Results: Notably, MRP2 V417I (c.1249G>A) variant showed a strong association with the CNS adverse drug reaction caused by carbamazepine (P = 0.009). In the logistic regression analysis using multiple variables, the relative risk of central nervous system ADR caused by carbamazepine was a 4.74-fold higher in the patients having V417I allele (p=0.006). The functional study using a FACScan flow cytometer revealed that V417I variation selectively reduced carbamazepine transport across cell membrane.Conclusions: These data strongly suggest that V417I polymorphism in the human MRP2 gene is associated with altered drug responses of carbamazepine.