Antiepileptic Drugs (Aeds) Polypharmacy Could Lead to Buried Pharmacokinetic Interactions Due to CYP450
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Send Orders of Reprints at [email protected] Drug Metabolism Letters, 2012, 6, 207-212 207 Antiepileptic Drugs (AEDs) Polypharmacy Could Lead to Buried Pharmacokinetic Interactions due to CYP450 Z. Tolou-Ghamari* Isfahan Neuroscience Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Abstract: CYP450 enzymes are basics for the metabolism of several medications such as numerous AEDs. As AEDs polypharmacy could lead to hidden pharmacokinetic interactions due to CYP450, therefore, the aim of this study was to determine a proper guideline for AEDs prescription in Iranian epileptic population. A cross-sectional study of fifty-four patients’ (n=23 females; n= 31 males with a mean age of 27 years) located in the Epilepsy Ward of Kashani Hospital of Isfahan University of Medical Sciences was carried out during the year 2011. Variables including sex, age, age of seizure onset, type and number of AEDs were recorded in d-Base. Results showed that the number of prescriptions based on AEDs polypharmacy was 77.8%. The most important drugs in prescriptions were carbamazepine (n=41) that is a potent inducer of CYP450 and valproic acid (n=31) that is a potent inhibitor of CYP450 simultaneously. Administration of AEDs was based on: three (n=17), four (n=7), five (n=4) or six (n=3) AEDs simultaneously. To avoid side effects, in prescribing AEDs that act as CYP450inhibitors or inducers concomitantly, their spectrum of interactions should be predicted. Keywords: AEDs, polypharmacy, CYP450, inducer, inhibitor. INTRODUCTION sufficiently manage their seizures. There is association between commencement, persistence and discontinuation of Epilepsy is a recurrent neurological disorder AEDs [7]. distinguished by seizures [1]. Because the efficacies of antiepileptic drugs (AEDs) are often equivalent, its Advances in the understanding of AEDs mechanisms of prescription is often determined by adverse effects and has action have discovered two major patterns increasing benefited from a comparable acceleration in our under- inhibition either through gamma-aminobutyric acid (GABA) standing of the essential processes underlying neuronal or glycine, or decreasing excitation due to glutamate. excitability and management [2,3]. As previous publication However, some AEDs reduce membrane excitability by reported that the concurrent use of multiple drugs or interrelating with neurotransmitter receptors or ion channels polypharmacy could cause adverse effects [3], therefore in but the methods of action for most of them are not fully treatment of epilepsy, monotherapy continues as the “gold understood [8,9]. Sodium channels in neurons are standard” [4]. Nonetheless, the complication of clinical responsible for the rising phase of action potentials. In examinations supported monotherapy and the rationale for seizure there is excess depolarization due to a persistent in which these examinations are intended, express it complicated sodium currents. Carbamazepine, phenytion, primidone and to evaluate the realistic allegations of these data [5]. The perhaps sodium valproate reduce high rate frequent firing of assortment of an antiepileptic drug is assisted by the develop alarming by sodium channel limitation (oxcarbazepine) awareness of syndrome-specific effectiveness, the probability and potentiate GABA receptors. The enzyme glutamic acid of potential side effects, and a vigilant threat profit decarboxylase restores glutamate into GABA. Valproic-acid evaluation modified to each patient. Subsequently, variations and gabapentin are recognized to increase the production of in techniques for classification adverse effects, discrepancies GABA. Gabapentin connects to a self-important semblance in the populations studied, and incompatible classifications site on neuronal membranes in a limited region part of of adverse effects make it difficult to recognize how to the central nervous system (CNS). This binding site may use information on adverse effects to choose AEDs [6]. A be linked to a potential energetic transport procedure of high percentage of patients with resistant epilepsy are treated gabapentin into neurons; however, this has not been with polypharmacy, which probably benefit only a minority confirmed and the mechanism of action of gabapentin of them. Conservative insight would recommend that leftovers tentative. Lamothrigin extends inactivation of patients should be judged for combination treatment only voltage-dependent sodium-channels and reserved the when chronological monotherapy schedules have failed to discharge of glutamate and aspartate. It is less efficient in the reserve of acetylcholine or GABA removal. Lamothrigin reduces steady elevated incidence chronic firing of voltage- *Address correspondence to this author at the Isfahan Neuroscience dependent sodium action potentials that may effect in a Research Centre (INRC), Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Tel/Fax: +98 311 6291050; special reduced discharge of presynaptic glutamate [10]. E-mail: [email protected] Topiramate blocks the action potentials obtained repetitively 1874-0758/12 $58.00+.00 ©2012 Bentham Science Publishers 208 Drug Metabolism Letters, 2012, Vol. 6, No. 3 Z. Tolou-Ghamari by a sustained depolarization of the neurons in a time- included prescriptions based on monotherapy, cluster 2 dependent manner, suggesting a state-dependent sodium with 2-3 and cluster 3 with more than 3 AEDs respectively. channel blocking action. Topiramate also increases the Table 1 shows hidden pharmacokinetic interactions within action of the GABA (controls an important chloride channel) clusters 2&3. All data were recorded initially in dBase and and reveals antagonism of the glutamate excitatory amino processed using Microsoft Excel and SPSS (version, 18.0) acid receptor [11]. The mode of action of clonazepam is to for windows. The variables of interest were sex, age, age of assist GABAergic situated in the brain [12]. Levetiracetam seizure onset, type and number of AEDs used by each joins to a synaptic vesicle protein, which is supposed to patient. Descriptive statistics included; calculation of means, obstruct nerve transmission across synapses [13]. Clobazam range, frequency and proportions for categorical ones. is a long-acting 1,5-benzodiazepine and it's anticonvulsant properties are connected with allosteric commencement of RESULTS the ligand-gated GABA receptor [14]. The main mechanism Approximately 15 varieties of AEDs (both generic and of action of phenobarbital is supposed to be their affinity for brand-name) have been used for the treatment of epilepsy. the GABA receptor and potentiate the effect of GABA at this Mean age of epilepsy onset was 15.6 years (range: birth-74 receptor. In addition to this GABAergic effect, it also blocks years). An epileptic attack was occurred around six (25%), a subtype of glutamate receptor [15]. Zonisamide acts as an eleven (50%) and seventeen years of life (75%) respectively. enhancer of GABA discharge and an inhibitor of glutamate Preliminary analysis of AEDs within medical prescriptions release. Zonisamide also inhibits voltage-gated sodium implicated that valproic acid (n=41) > carbamazepine (n=31) channel and T-type calcium channel [16]. > phenytoin (n=18) > lamothrigin (n=15) > topiramate Cytochrome P450 (CYP450) enzymes are fundamentals (n=14) > clonazepam (n=8) >levetiracetam (n=7) > clobasam for the metabolism of various AEDs. Inhibitors block the (n=6) > primidone (n=5), zonisamide (n= 5) > phenobarbital metabolic activity of one or more CYP450 enzymes and (n=3) > ethosuximid (n=2), gabapentin (n=2), risperidone inducers increases CYP450 enzyme activity by increasing (n=2), oxcarbazepine (n=1). Prescriptions were concentrated enzyme synthesis. on two compounds, carbamazepine (n=41) and valproic acid (n=31). Treatment of epileptic patients with AEDs based on polypharmacy, could be influenced by induction or The number of AEDs used by each patient ranged from inhibition of the CYP450 system. Even regular AEDs doses one to six with a mean of three. As described in methods may cause toxicity related to elevated drug serum levels if a section, cluster 1 (monotherapy) included 22.2 %, cluster 2 person is a poor metabolizer or has a CYP450 enzyme integrated 51.9% and cluster 3 incorporated 25.9% of AEDs inhibitor added to therapy. Potent inductors of CYP450 prescriptions (see Fig. 1). isoenzymes are carbamazepine, phenobarbital, phenytoin, As shown in Table 1, combination therapy based on two and primidone. Oxcarbazepine and topiramate are weak PID PIH AEDs such as; carbamazepine /valproic acid (n=6), inductors of the CYP isoenzyme 3A4, whereas they inhibit valproic acid PIH /phenobarbital PID (n=2), carbamazepine PID CYP2C19. Valproic acid is a potent inhibitor of several CYP /phenytoin PID (n=1), valproic acid PIH/topiramate WI (n=1), isoenzymes and glucuronyltransferases. Antiepileptics that phenytoin PID /valproic acid PIH (n=1) and so on. are not involved in drug interactions include gabapentin and levetiracetam [17, 18]. Administrations based on three AEDs were determined as: carbamazepine PID /valproic acid PIH /topiramateWI(n=2), Pharmacokinetic interactions between AEDs emerge to PID PID WI be responsible for the superior effectiveness or side effects carbamazepine /phenytoin /topiramate (n=1), carbamazepine PID /primidone PID /valproic acid PIH (n=1), [6]. In Iranian epileptic population, there are controversial PID WI PID data suggesting that AEDs