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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 (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, and to evaluate the realistic allegations of these data [5]. The perhaps sodium reduce high rate frequent firing of assortment of an antiepileptic drug is assisted by the develop alarming by limitation () 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 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] 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 is to for windows. The variables of interest were sex, age, age of assist GABAergic situated in the brain [12]. 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]. range, frequency and proportions for categorical ones. is a long-acting 1,5- and it's 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 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]. 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]. > (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 polypharmacy has advantage over primidone /topiramate /phenytoin (n=1) and so on. monotherapy. Useful clinical data on the quality of AEDs, its There were prescriptions based on four AEDs (n=7). proper direction policies and the adverse effects should be Some documented prescriptions in this group involved as; identified. As prescription of AEDs continues to increase, carbamazepine PID /valproic acid PIH/topiramate WI/zonisamide systematic study associated to prescription in terms of (n=1), carbamazepine PID /valproic acid PIH/topiramate WI t PID monotherapy or polypharmacy and appropriate drug /lamothrigin 1/2 of other AEDs (n=1), carbamazepine management strategy is of interest to be investigated. /topiramate WI /clobasam/lamothrigin T1/2 of other AEDs (n=1) and etc. PATEINTS Prescription based on five AEDs (n=4) intended as: In a cross-sectional manner, fifty-four patients carbamazepine PID /topiramate WI/valproic acid PIH /lamothrigint Cconstant PID (comprised 23 females and 31 males) with a mean age of 27 1/2 of other AEDs /levetiracetam (n=1), carbamazepine years (range; 7-74 years) located at the Epilepsy Ward of /phenytoin PID /valproic acid PIH /clobasam/lamothrigin (n=1), Isfahan Kashani Hospital was carried out during the year topiramate WI/valproic acid PIH//phenobarbital PID t 2011. The study was approved by the Isfahan Neurosciences /lamothrigin 1/2 of other AEDs (n=1). Research Centre Committee (INRCC). Prescriptions based on six AEDs (n= 3) such as; carbamazepine PID /topiramate WI/phenytoin PID/gabapentin METHODS Cconstant t /clonazepam/lamothrigin 1/2 of other AEDs (n=1) and In order to taking 1, 2, 3, 4, 5 and 6 AEDs used by each so on. patient concurrently, three clusters were made. Cluster 1, Antiepileptic Drugs (AEDs) Polypharmacy Could Lead to Buried Drug Metabolism Letters, 2012, Vol. 6, No. 3 209

Table 1. Drug Details (Based on Hidden Interaction) in a Number of Prescriptions with 2-3 (Cluster 2) or >3 AEDs (Cluster 3)

Patient’s Code No Types of Oral AEDs in Each Prescription Predicted PK Interactions (Reference 1-43)

PID PIH 3,20,24,25,48,34 CBZ / VP Same place for metabolism-C0CBZ-E/ C0CBZ, CNS toxicity of CBZ - C0VP - The risk of convulsion still remains challenging and is 

PID PID 6 CBZ / PHT C0CBZ-E/ C0CBZ -C0 of both CBZ and PHT - The risk of Convulsion is 

11 VP PIH / TOP weak inhibitor of CYP2C19 and weak inducer of Same place for metabolism- VP as a potent inhibitor blocks the metabolic activity CYP3A4 of both AEDs. VP and TOP together or alone can cause hyperammonemia with or without encephalopathy.

8,54 PHENO PID / VP PIH Same place for metabolism - PHENO a potent inducer and VP a potent inhibitor

could result to an increase in toxicity of PHENO due to C0metabolite-C0VP  - The risk of convulsion still remains challenging and is 

PID PIH 12 PHT / VP Same place for metabolism - VP dislocate PHT from its biding site-C0 PHT - PHT toxicity

t t 7 CBZ / TOP/ LAMO 1/2 of other AEDs LAMO 1/2 of other AEDs –CBZ-E/CBZ  -parent C0CBZ- TOP CL - C0 TOP- The risk of convulsion still remains challenging and is 

9 CBZ / PHT/ TOP In combination therapy of carbamazepin and phenytoin, C0 of both drugs- two

potent inductors might cause topiramate C0 - The risk of convulsion still remains challenging.

16 CBZ / PHT/ LAMO In CBZ polypharmacy the amount of metabolite is high. PHT could C0 CBZ and t in turn CBZ could C0 PHT- LAMO 1/2 of other AEDs – Decrease in C0 of AEDs in this combination could increase the risk of convulsion.

21,35 CBZ / VP / TOP CNS toxicity of CBZ  due to  in CBZ-E- C0VP - The risk of Convulsion -addition of TOP- may cause hyperammonemia with or without encephalopathy.

41 CBZ / VP / LAMO No points with CBZ and VP in combination of three, CBZ and VP interfere with LAMO metabolism-VP  LAMO CL in most patients-Dosage of LAMO should be reduced to half.

43 CBZ / VP /PRIM PID In the presence of two potent inductor and one potent inhibitor, CNS toxicity of

CBZ - C0VP - The risk of Convulsion 

51 PHT / VP / CLOB VP dislocate PHT from its biding site-C0 PHT - PHT toxicity 

52 PHT / VP / LAMO PHT and VP interfere with LAMO metabolism-VP  LAMO CL in most patients- Dosage of LAMO should be reduced to half

57 PHT /PRIM / TOP PHT may cause C0PRIM- intoxication by the primidon metabolite phenobarbital- addition of TOP increase toxicity.

19,22 CBZ / VP / TOP / ZONI

39 CBZ / VP / PRIM / LEV 1) Use of >3 AEDs concurrently  PK interactions 2) PK interactions could cause toxicity 5 CBZ / VP / LAMO / ZONI / LEV 3) The risk of convulsion still remains challenging.

36 TOP / VP / PHENO / LAMO / ETHO Not recommended 45 CBZ / TOP / VP / LAMO / LEV PK interactions

50 CBZ / PHT / VP / LAMO / CLOB Deteriorate clinical outcome

15 CBZ / TOP / PHT / GABA / LAMO / CLON

Abbreviations: PID=Potent Inductor; PIH=Potent Inhibitor WID= Weak Inductor; Not Known Effect on CYP=Cconstant PK=pharmacokinetics; CL= Clearance; CBZ=carbamazepine; CBZ-E=carbamazepine-epoxide VP=valproic acid; PHT=phenytoin; TOP=topiramate; LAMO=lamothrigin; PHENO=Phenobarbital; CLOB=clobasam;PRIM=primidone; CLON=clonasepam; ZONI=zonisamide; LEV=levitiracetam; ETHO=Ethosuximide; GABA= Gabapentin

DISCUSSION Previous publication reported that CYP450 enzymes could be inhibited or induced by a number of AEDs. This study confirms that in Iranian epileptic population to However balanced AEDs polypharmacy aim at multiple prevent therapeutic failure due to pharmacokinetics receptors or ion channels to increase inhibition and interaction (as a result of inhibition or induction of CYP simultaneously reduce excitation but many interactions are 450), rational combinations of AEDs is essential. 210 Drug Metabolism Letters, 2012, Vol. 6, No. 3 Z. Tolou-Ghamari

Fig. (1). Number of AEDs used by each patient. Group 1 indicated patient with 1 AED, Group 2 with 2-3 AEDs and group 3 with >3 AEDs. the result of polypharmacy due to an alteration in CYP450 The main pathways of biotransformation for carbamazepin metabolism [3, 19, 20]. The clinical situation related to these are epoxidation, glucoronidation, hydroxylation and events could produce AEDs toxicity such as encephalopathy, sulfuration. The drug is completely metabolized and the lethargy, somnolence, ataxia, and cognitive dysfunction. main metabolite is carbamazepin-epoxide. It seems in Therefore in AEDs combinations, attention to synergic polypharmacy the blood concentration of carbamazepin- efficacy and avoidance of neurotoxicity is compulsory [21, epoxide / carbamazepin is higher than monotherapy. 22]. When two AEDs, both require the same enzyme for Carbamazepine, is a strong inductors of CYP isoenzymes metabolism, are given concurrently, one AED may inhibit or mainly glucuronyltransferases, thus declining not only its induce metabolism of the other, and thus an adverse drug own plasma level (parent drug) and efficacy but also that of interaction may occur [17, 18]. Many factors determine the other antiepileptics and other drugs. Serum carbamazepine relative effects of one AED on the metabolism of another C0 could diminish and carbamazepine-10,11-epoxide drug. Drug concentration and relative enzyme affinity metabolite could increase. Afterward, the clearance of determine metabolic drug interactions. Significant inter- valproic acid increase and then its C0 diminish which could patient variability exists with respect to the enzymatic be clinically troublesome. In this clinical circumstance activity of the CYP450 isoenzymes. carbamazepine should be discontinued to answer in increased valproic acid absorptions [6,24-28]. Despite the documented guidelines for AEDs management, the issue of monotherapy or polypharmacy, In prescription based on valproic acid (potent inhibitor of CYP450) therapeutic drug concentrations and pharmacokinetic /topiramate weak inhibitor of CYP2C19 and weak inducer of CYP3A4 (see Table interactions need further investigation in Iranian epileptic 1 patient with code No; 11), the possibility that simultaneous population. Particular awareness must be compensated to administration could connected to hyperammonemia with or decrease the number of AEDs and examine for competence without encephalopathy is strong. Clinical signs of and toxicity [6, 21-23]. hyperammonemic encephalopathy regularly comprise sharp An elevated rate of offensive AEDs combinations, variations in stage of awareness, cognitive utility through prescribed for epileptic patients have been identified. The lethargy, nausea and hypothermia [6, 29-31]. limitations for judgment in order to correlate AEDs dose to Concomitant administration of valproic acid (potent inhibitor of CYP450) (potent inductor of CYP450) C0 (trough level) was the lack of therapeutic drug monitoring /phenobarbital (see Table 1 patients results. with code No; 8, 54) can result in augmented plasma Due to pharmacokinetic interactions related to phenobarbital (C0) and extreme somnolence. Even devoid CYP450 metabolism, combination therapy based on: of generous augments in serum concentrations of each carbamazepinePID/valproic acidPIH(see Table 1 patients with drug, combination are able to produce sever CNS depression code No; 3, 20, 24, 25, 34, 48) necessitate additional [32]. deliberation. In simultaneous administration of valproic acid (potent inhibitor of CYP450) (potent inductor of CYP450) In this prescription, carbamazepin is a potent inductor of / phenytoin (see Table 1 CYP450 and valproic acid is a potent inhibitor of CYP450. patient with code No; 12), valproic acid dislocate phenytoin Antiepileptic Drugs (AEDs) Polypharmacy Could Lead to Buried Drug Metabolism Letters, 2012, Vol. 6, No. 3 211 from protein binding and restrain its metabolism. [4] Guberman, A. Monotherapy or polytherapy for epilepsy? Can. J. Combination therapy in this patient may be associated with Neurol. Sci., 1998, 25(4), S3-8. [5] Arroyo, S.; Perucca, E. 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Received: July 27, 2012 Revised: October 20, 2012 Accepted: November 02, 2012