Lack of Association between the C3435T Polymorphism in the Human Multidrug Resistance (<i>MDR1</i>) Gene and Response to Antiepileptic Drug Treatment (2006)

To the Editor: We read with great interest the manuscript by Sills and colleagues (1), who investigated association between the C3435T polymorphism in the human multidrug resistance ABCB1 (previously MDR1) gene and response to antiepileptic drug (AED) treatment. However, several significant items from this article should be discussed. In their study, the authors investigated clinical response to AED therapy in 400 patients, irrespective of individual drug exposure. This is the major restricting factor in this work, which can jeopardize all possible conclusions. Valproate (VPA) is not a substrate of P-glycoprotein (PGP), and therefore an association between the polymorphism of ABCB1 (MDR1) gene and a response to VPA therapy cannot be investigated (2). As no data were in this work were about the kinds of AEDs the patients were taking, it is highly possible that some of them were taking VPA, which compromises the results of this work. Furthermore, the authors did not mention anything about possible combinations of the AEDs that the patients were using. Some suggestions are found in the literature that different AEDs can have inhibitory or stimulatory effects on the function and expression of PGP (3). The possible effect of PGP polymorphism on a clinical response to pharmacotherapy is a very important issue in the contemporary approach to treating epilepsy. Therefore before establishing the effect of PGP on the AED polytherapy, its precise effect on each AED monotherapy must be established. Even more important, the authors did not pay attention to some concomitant medications in their group of patients. It is well known that some of the widely consumed drugs (verapamil, nifedipine, diltiazem, nicardipine, amiodarone, propranol, trifluoperazine, chlorpromazine, erythromycin, ceftriaxone, steroids, reserpine, etc.) are inhibitors of PGP (2,4). Coadministration of these drugs with AEDs can significantly influence the results of the study. Furthermore, only the patients with a history of alcohol-related seizures were excluded from the study, which leaves the possibility that the patients with symptomatic epilepsy (underlying tumors, cortical dysgenesis, cerebrovascular stroke, hippocampal sclerosis, etc.) were included (5). Such symptomatic epilepsies are difficult to treat regardless of any other factors, including polymorphism of the ABCB1 gene. Finally, a high percentage of nonresponders (57.5%) is at variance with the generally accepted standpoint in literature of ∼20–30% of the nonresponders (5,6). That raises the possibility that AED therapy was not appropriate in a certain percentage of the patients, and the results of the whole study are again at issue. Strong evidence is found in the literature, based on animal, in vitro, and human models, that C3435T polymorphism of the ABCB1 gene is associated with the response to the AED treatment (7,8). Nevertheless, some studies also claim the opposite results. Therefore to reach a definitive answer on this important question, the studies that investigate the association between C3435T polymorphism in the ABCB1 gene and AED therapy must exclude all other possible factors that can influence the results. The influence of the C3435T polymorphism of the ABCB1 gene on the clinical effect of each AED must be thoroughly investigated before we can start to investigate the combination of drugs or even combinations of several other factors.