Metabolism Of Antiepileptic Drugs Research Articles

Peculiarities of the effect of antiepileptic drugs on seizures in mice with corneal kindling against the background of low-dose premedication with carbamazepine and sulthiame

The aim. The aim of the study was to evaluate the effectiveness of antiepileptic drugs (AED) with a different mechanism of action against the background of prior use of low doses of carbamazepine and sultiam in the model of corneal kindling in mice. Materials and methods. The corneal kindling model in mice was used. The convulsive model was reproduced under the parallel preliminary administration of carbamazepine and sulthiame 30 minutes before electrostimulation. The anticonvulsant activity of AED (sulthiame, levetiracetam, carbamazepine, valproate, lamotrigine and retigabine) was studied under conditions after the formation of a stable syndrome of the generalised convulsive activity. Results and discussion. The administration of carbamazepine and sulthiame drugs modulates the activity of the cytochrome P450 enzyme system. Thus, carbamazepine in the dose of 7 and 12 mg/kg showed no significant anticonvulsant activity (the convulsive intensity – 4.42±0.25 points; 4.44±0.32 points) after its preliminary chronic administration, the same doses of carbamazepine showed a noticeable anticonvulsant effect in the control group of animals (3.52±0.26 points; 3.2±0.6 points, respectively). The anticonvulsant activity of lamotrigine changed both in the case of the preliminary chronic administration of an inducer (carbamazepine), and an inhibitor (sulthiame) of the cytochrome P450 system. Conclusion. Changes in the pharmacological effects of AED observed against the background of chronic administration of carbamazepine and sulthiame, in our opinion, may be due to both the modulation of the cytochrome P450 system and other groups of enzymes involved in the AED metabolism

The role of DNA-profiling in predicting anticonvulsant-induced QT prolongation diseases based on pharmacogenetic aspects

Anticonvulsants or antiepileptic drugs (AEDs) are widely used for various neurological and psychiatric diseases and are often prescribed for a long period. In this regard, the issue of their safety profile is acute, including risk assessment for the development of life-threatening conditions and adverse drug reactions (ADRs). From the point of view of personalized medicine, it is important to develop an interdisciplinary approach to the development of a new strategy for a personalized approach to predicting AED-induced prolongation of the QT interval as one of the most unfavorable prognostic cardiac ADRs (including sudden death syndrome — SDS). We searched the databases of full-text publications for the period from 2012 to 2022 for keywords and their combinations. We have discovered and systematized monogenic and multifactorial forms of long QT syndrome (LQTS) and candidate genes that slow down AEDs metabolism in the liver. Identification of risk alleles of single nucleotide variants (SNV) of candidate genes predisposing to the development of AED-induced LQTS and SDS will allow adjusting the choice and dosage of these drugs and preventing the development of the ADR, which will improve the quality of life and help prevent SDS in patients with mental and neurological disorders

CYP2C9 (*2&*3) and CYP2C19 (*2&*3) polymorphisms among children with nonlesional epilepsy: a single-center study.

Cytochrome (CYP) P450 enzymes are responsible for metabolism of antiepileptic drugs (AEDs), and encoded by highly polymorphic genes. A case-control study was conducted in Mansoura University Children's Hospital, Egypt including 100 children with nonlesional epilepsy (50 AEDs responders and 50 resistant cases) and 50 healthy controls. All participants were investigated for frequencies of CYP2C9 (*2&*3) and CYP2C19 (*2&*3) genotypes and alleles using polymerase chain reaction. The current study reported higher frequencies of CYP2C9*2 (CT) genotype and (T) allele among responsive and resistant groups than controls (P < 0.001). Frequency of (TT) genotype was higher in resistant than responsive group (P = 0.02, OR 12, 95% CI 1.2-122.3). No significant differences were detected between responsive and resistant groups regarding CYP2C9*2 alleles (P = 0.2). CYP2C9*3 (AC) genotype was more frequent in controls than other groups (P < 0.001). No significant differences were detected between responsive and resistant groups regarding neither CYP2C9*3 genotypes nor alleles (P = 0.11 and 0.2, respectively). CYP2C19*2&*3 (GA) genotypes and (A) alleles were more frequent in responsive and resistant groups than controls (P < 0.001). No significant differences were detected between responsive and resistant groups regarding neither CYP2C19*2&*3 genotypes nor alleles (P = 0.21 and 0.89 for CYP2C19*2; P = 1 and 0.77 for CYP2C19*3). The CYP2C9*2 (TT) genotype, earlier seizure onset and higher seizures frequency were associated with higher risks of refractory epilepsy. We concluded that heterozygous genotypes of CYP2C9*2 and CYP2C19 (*2&*3) and mutant alleles of studied variants were more frequent among children with nonlesional epilepsy. CYP2C9*2 (TT) genotype increased refractory epilepsy susceptibility.

Selecting Hormonal Contraceptives in Women Taking Antiepileptic Drugs : Review of Literature and Practical Recommendations

Contraception is a very important issue in women with epilepsy, since very broad questions taken in applying it to prevent unplanned pregnancy. The choice of contraceptive methods must be related to how the mechanism of action of antiepileptic drugs (AEDs), the contraceptive itself, and both interactions. Hormonal contraception can induce metabolism of AEDs and lead to increasing of seizure frequency, and in the other hand AEDs may decrease the blood levels of hormonal contraception. Therefore, physician must consider the type of contraception being used before prescribing AEDs. Additionally, they should emphasize the interaction between them in counseling, to assure that women with epilepsy have time to decide which type will be best use for them. This challenging matter needs better recommendation for practice, both neurologist and gynecologist.Keywords: antiepileptic drug, contraception, women with epilepsy

Selecting Hormonal Contraceptives in Women Taking Antiepileptic Drugs : Review of Literature and Practical Recommendations

Contraception is a very important issue in women with epilepsy, since very broad questions taken in applying it to prevent unplanned pregnancy. The choice of contraceptive methods must be related to how the mechanism of action of antiepileptic drugs (AEDs), the contraceptive itself, and both interactions. Hormonal contraception can induce metabolism of AEDs and lead to increasing of seizure frequency, and in the other hand AEDs may decrease the blood levels of hormonal contraception. Therefore, physician must consider the type of contraception being used before prescribing AEDs. Additionally, they should emphasize the interaction between them in counseling, to assure that women with epilepsy have time to decide which type will be best use for them. This challenging matter needs better recommendation for practice, both neurologist and gynecologist.Keywords: antiepileptic drug, contraception, women with epilepsy

The genetic methods for drug-resistant epilepsy

Background: Mechanisms of underlying pharmacoresistance have been explored insufficiently. Enzymes of a system for biotransformation of xenobiotic and transporters for drugs are the key participants in the systems of metabolism of antiepileptic drugs (AEDs). Among proteins-transporters, glycoprotein P encoded by MDR1 gene plays an essential role in the processes of uptake, distribution and excretion of AEDs.

Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy.

Identified the polymorphisms of CYP2D6, CYP2C9, CYP2C19 and CYP3A4, within a rigorously selected population of pediatric patients with drug-resistant epilepsy. The genomic DNA of 23 drug-resistant epilepsy patients and 7 patients with good responses were analyzed. Ten exons in these four genes were genotyped, and the drug concentrations in saliva and plasma were determined. The relevant SNPs with pharmacogenomics relations were CYP2D6*2 (rs16947) decreased your activity and CYP2D6*4 (rs1065852), CYP2C19*2 (rs4244285) and CYP3A4*1B (rs2740574) by association with poor metabolizer. The strongest risk factors were found in the AA genotype and allele of SNP rs3892097 from the CYP2D6 gene, followed by the alleles A and T of SNPs rs2740574 and rs2687116, respectively from CYP3A4. The most important concomitance was between homozygous genotype AA of rs3892097 and genotype AA of rs2740574 with 78.3% in drug-resistant epilepsy patients as compared to 14.3% in control patients. The results demonstrated the important role of the CYP 3A4*1B allelic variant as risk factor for developing drug resistance and CYP2D6, CYP2C19 SNPs and haplotypes may affect the response to antiepileptic drugs.

The genetic methods for drug-resistant epilepsy

ActualityMechanisms of underlying pharmacoresistance have been explored insufficiently. Enzymes of a system for biotransformation of xenobiotic and transporters for drugs are the key participants in the systems of metabolism of antiepileptic drugs (AEDs). Among proteins-transporters, glycoprotein P encoded by MDR1 gene plays an essential role in the processes of uptake, distribution and excretion of AEDs.ObjectiveThe work initiated to study gene MDR1 C3435 T polymorphism and to assess its association with pharmacoresistance formation in patients with epilepsy receiving antiepileptic drugs (AEDs).MaterialsStudy involved 89 patients with localization-related epilepsy and 55 unrelated healthy subjects.ResultsDistribution of 3435 T/C polymorphism in NDR1 gene was analyzed in the patients with the localization-related epilepsy and nominally healthy donors. The distribution of frequencies of gene alleles was found to correspond to the Hardy-Weinberg equilibrium (Р &gt; 0.05). Incidence of genotypic variants of the polymorphism was as follows, СС was found in 18.6%, СТ and TT were observed in 55.9% and 25.4% of cases. In the controls СС was found in 60.0%, СТ and TT were observed in 33.3% and 6.6% of cases, respectively. The findings are the evidence for significant effect of functionally weak variants in C3435 T polymorphism of MDR1 gene on efficacy of antiepileptic therapy.Conclusionpresence of T-allele of C3435 T polymorphism of MDR1 gene increases risk of pharmacoresistance in the patients with epilepsy and is a significant and predicting criterion of efficacy and feasibility of the antiepileptic therapy conducted.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Contraception in women with epilepsy: Potential drug interactions between contraceptive hormones and enzyme inducing antiepileptic drugs

Contraception is essential for a woman as it helps to achieve autonomy in personal life and avoid unwanted pregnancy. Adequate contraception is even more essential for women with epilepsy (WWE) due to potential maternal and fetal risks of antiepileptic drugs (AEDs) and poor seizure control. There are several hormonal and nonhormonal contraceptive options available for WWE, with combined oral hormonal pills being used most commonly. The choice of contraception in WWE is influenced by many factors, chief among these being potential drug interactions between contraceptive hormones and enzyme inducing antiepileptic drugs (EIAEDs). While EIAEDs may increase metabolism of contraceptive hormones leading to contraceptive failure, contraceptive hormones in turn may increase metabolism of AEDs resulting in their faster elimination and breakthrough seizures. The co-administration of lamotrigine and oral hormonal pills is especially complicated by unpredictable interactions and requires several considerations. In this review, we try to address various issues concerning the use of different contraceptive modalities in WWE. In addition, we review the current guidelines for concurrent use of hormonal contraception and AEDs in WWE.

Controversies in contraception for women with epilepsy.

Contraception is an important choice that offers autonomy to women with regard to prevention of unintended pregnancies. There is wide variation in the contraceptive practices between continents, countries, and societies. The medical eligibility for contraception for sexually active women with epilepsy (WWE) is determined by the type of anti-epileptic drugs (AEDs) that they use. Enzyme inducing AEDs such as phenobarbitone, phenytoin, carbamazepine, and oxcarbazepine increase the metabolism of orally administered estrogen (and progesterone to a lesser extent). Estrogen can increase the metabolism of certain AEDs, such as lamotrigine, leading to cyclical variation in its blood level with resultant adverse effect profile or seizure dyscontrol. AEDs and sex hormones can increase the risk of osteoporosis and fracture in WWE. The potential interactions between AEDs and hormonal contraception need to be discussed with all women in reproductive age-group. The alternate options of oral contraception such as intrauterine copper device, intrauterine levonorgestrel release system, and supplementary protection with barriers need to be presented to them. World Health Organization has recommended to avoid combination contraceptive pills containing estrogen and progesteron in women who desire contraception and in breastfeeding mothers. Care providers need to consider the option of non-enzyme-inducing AEDs while initiating long-term treatment in adolescent and young WWE.

Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.

Prevention of Fetal Congenital Malformations with Allowance for the Pharmacogenetic Features of the Metabolism of Antiepileptic Drugs and Hereditary Abnormalities in the Folate Cycle

Fetal congenital malformations are among the most dangerous complications of pregnancy in women with epilepsy taking antiepileptic drugs. Valproic acid and phenobarbital have the greatest risk of teratogenic effects. Insights into the current mechanisms of teratogenic effect of antiepileptic drugs, pharmacogenetic features of the metabolism of valproates and hereditary abnormalities in the folate cycle enables prevention of fetal congenital malformations.

Genetic polymorphisms associated with antiepileptic metabolism.

Several factors, including pharmacogenetics, contribute to inter-individual variability in drug response. Many antiepileptic drugs (AEDs) are metabolized by a variety of enzymatic reactions, and the cytochrome P450 (CYP) family has attracted considerable attention. Some of the CYPs exist as genetic (allelic) variants, which may also affect the plasma concentrations or drug exposure. Regarding the metabolism of AEDs, the polymorphic CYP2C9 and CYP2C19 are of particular interest. There have been recent advances in discovering factors such as these, especially those underlying the risk of medication toxicity. This review summarizes the evidence about whether such polymorphisms affect the clinical action of AEDs to facilitate future studies on the pharmacogenetics of epilepsy. We performed Key Words searches in the public databases PubMed, Medscape, and Rxlisty, Pharm GKB for genetic polymorphisms and the NCBI website for the nomenclature of alleles of CYP450, finding that CYP2D6, CYP2C9, CYP3A4, and CYP2D19 were involved in the metabolism of most antiepileptic drugs, given the allele frequency in the population and the associated variability in the clinical response.

Farmacogenética y metabolismo de fármacos antiepilépticos: implicación de variantes genéticas en citocromos P450

Antiepileptic drugs (AEDs) are used for the seizures control in patients with epilepsy, however 20-30% of epileptic patients are drug resistant. Several factors contributing to the variability of the AEDs response, and this variability can be partially attributed to the presence of sequence variations (polymorphisms) in genes encoding enzymes involved in the AEDs metabolism. To describe the polymorphisms in genes that encoding for proteins involved in the metabolism of some of the major AEDs, focusing on enzymes cytochrome P450 (CYP450). There are some polymorphisms in genes encoding proteins involved in drug metabolism, particularly enzymes of superfamily CYP450, that are already considered of clinical utility in the therapeutic management. These genetic variants contribute to the variability of the activity of metabolizing enzymes, which in turn influencing the poor or inadequate therapeutic response, as well as in the occurrence of adverse effects. The identification of interindividual variability in the response to AEDs may allow the personalized treatment with the aim of maximize the efficiency and minimize risk, regardless of the clinical variability and adverse effects could be manifest in a minority of the patients.

Antiepileptic drugs in women with epilepsy during pregnancy.

Prescribing antiepileptic drugs (AEDs) in pregnancy is a challenge to the clinician. A multitude of questions arise that must be addressed even prior to conception. In women with proven epilepsy, it may be dangerous to stop or even change the AED regimen during pregnancy. Changes could lead to injury or death in both the mother and the fetus. In the rare cases when discontinuing an AED is plausible, it should be done methodically in consultation with the physician prior to conception. Most women with epilepsy are consigned to continue their AEDs before, during and after pregnancy. The metabolism of AEDs may change drastically during pregnancy. These changes must be addressed by the clinician. Drug levels should be monitored consistently during pregnancy. The risks to the fetus must be delineated in terms of side effects from specific drugs as well as risks from the seizure disorder itself. Many AEDs have well known teratogenic effects, and these must be elucidated to the mother. There are risks (theoretical and evidence based) for obstetrical complications, poor neonatal outcomes, congenital malformations and even cognitive effects on the child later in life. These risks are addressed in this article with respect to individual AEDs. Recommendations include but are not limited to preconception counseling, taking folate pre and post conception, prescribing the most effective AED while minimizing risks, and avoiding polytherapy and valproate if possible.

Is breast‐feeding of infants advisable for epileptic mothers taking antiepileptic drugs?

Epilepsy is a relatively common maternal complication affecting 0.3-0.5% of pregnant women. For most mothers with epilepsy, the use of antiepileptic drugs (AED) is unavoidable, even during pregnancy and lactation. Therefore, the fetus is indirectly exposed to AED via the placenta and breast milk. AED are also prescribed for female patients with other diseases, such as bipolar disorders. In clinical settings, physicians are frequently questioned whether or not women patients taking AED should breast-feed their offspring. Thus, it is necessary to establish an optimum AED regimen for women taking AED, in particular for those with epilepsy during pregnancy and lactation. In this article, we critically review the effects of AED on infants via breast milk and attempt to provide suggestions for clinicians regarding these effects during breast-feeding, based on the data of transplacental passage of AED, breast milk concentration/maternal serum concentration ratios, AED metabolism in infants and the effects of AED in breast milk on infants.

Genetic factors associated with drug-resistance of epilepsy: Relevance of stratification by patient age and aetiology of epilepsy

Epilepsy drug-resistance may depend on the metabolism of antiepileptic drugs (AEDs), transport to the epileptic focus and/or target sensitivity. Furthermore, drug response depends on multiple characteristics of the patient, the epilepsy, and the antiepileptic drugs used. We have investigated the association between polymorphisms related to antiepileptic drug metabolism (CYP2C9, CYP2C19, and UGT), transport (ABCB1), and targets (SCN1A) both in a crude analysis and after adjusting by clinical factors associated with drug-resistance, and stratifying by patient age or aetiology of epilepsy. Caucasian outpatients ( N = 289), children ( N = 80) and adolescent-adults ( N = 209), with idiopathic ( N = 69), cryptogenic ( N = 97) or symptomatic epilepsies ( N = 123) were selected when they had either drug-resistance (with at least four seizures over the previous year after treatment with more than three appropriate AEDs at appropriate doses) or drug responsiveness (without seizures for at least a year). Samples were genotyped by allelic discrimination using TaqMan probes. No significant association between polymorphisms and drug-resistance was found either in the crude analysis or in the adjusted analysis. However, adults with the ABCB1_3435TT or 2677TT genotypes had a lower risk of drug-resistance than those with the CC or the GG genotypes. Furthermore, patients with symptomatic epilepsies with the ABCB1_3435CT or TT genotypes had a lower risk of drug-resistance than those with the CC genotype. An opposite but insignificant tendency was found in children and in idiopathic epilepsies. Although replication studies will be needed to confirm our results, they suggest that stratification by patient age and by the aetiology of epilepsy could contribute to unmask the association between ABCB1 polymorphisms and drug-resistance of epilepsy.

Botanicals and Herbs: A Traditional Approach to Treating Epilepsy

Botanicals and herbs have a centuries-old tradition of use by persons with epilepsy, in many cultures around the world. At present, herbal therapies are tried by patients in developing as well as developed countries for control of seizures or adverse effects from antiepileptic drugs (AEDs), or for general health maintenance, usually without the knowledge of physicians who prescribe their AEDs. Well-designed clinical trials of herbal therapies in patients with epilepsy are scarce, and methodological issues prevent any conclusions of their efficacy or safety in this population. Furthermore, some botanicals and herbs may be proconvulsant or may alter AED metabolism. In spite of these limitations, further preclinical evaluation of botanicals and herbs and their constituent compounds using validated scientific methods is warranted based on numerous anecdotal observations of clinical benefit in patients with epilepsy and published reports showing mechanisms of action relevant to epilepsy or anticonvulsant effects in animal models of epilepsy. This review highlights the use of herbal therapies for epilepsy, outlines the role of the U.S. Food and Drug Administration in regulating herbal products, and presents the author's approach to the scientific assessment of herbal therapies as potential therapies for patients with epilepsy.

Treating seizures in renal and hepatic failure

INTRODUCTION: Renal and hepatic diseases cause seizures and patients with epilepsy may suffer from such diseases which change antiepileptic drugs (AEDs) metabolism. OBJECTIVES: To revise how seizures may be caused by metabolic disturbances due to renal or hepatic diseases, by their treatment or by comorbidities and how AEDs choice might be influenced by these conditions. RESULTS: Seizures arise in renal failure due to toxins accumulation and to complications like sepsis, hemorrhage, malignant hypertension, pH and hydroelectrolytic disturbances. Hemodialysis leads to acute dysequilibrium syndrome and to dementia. Peritoneal dialysis may cause hyperosmolar non-ketotic coma. Post-renal transplant immunosupression is neurotoxic and cause posterior leukoencephalopathy, cerebral lymphoma and infections. Some antibiotics decrease convulsive thresholds, risking status epilepticus. Most commonly used AEDs in uremia are benzodiazepines, ethosuximide, phenytoin and phenobarbital. When treating epilepsy in renal failure, the choice of AED remains linked to seizure type, but doses should be adjusted especially in the case of hydrosoluble, low-molecular-weight, low-protein-bound, low apparent distribution volume AEDs. Hepatic failure leads to encephalopathy and seizures treated by ammonium levels and intestinal bacterial activity reductions, reversal of cerebral edema and intracranial hypertension. Phenytoin and benzodiazepines are usually ineffective. Seizures caused by post-hepatic immunosupression can be treated by phenytoin or levetiracetam. Seizures in Wilson's disease may result from D-penicillamine dependent piridoxine deficiency. Porphyria seizures may be treated with gabapentin, oxcarbazepine and levetiracetam. Hepatic disease changes AEDs pharmacokinetics and needs doses readjustments. Little liver-metabolized AEDs as gabapentin, oxcarbazepine and levetiracetam are theoretically more adequate. CONCLUSIONS: Efficient seizures treatment in renal and hepatic diseases requires adequate diagnosis of these disturbances and their comorbidities besides good knowledge on AEDs metabolism, their pharmacokinetic changes in such diseases, careful use of concomitant medications and AEDs serum levels monitoring.

Antiepileptic drugs in pediatric epilepsy

The epilepsies are socially handicapping disorders and even a single seizure occurring in certain circumstances may have disastrous effect. The impact of epilepsy on every aspect of both the lives of the child and family is significant. Issues such as mental retardation, subtle neuropsychologic disturbances, cognitive problems, behavioral problems and learning difficulties are major factors affecting the children with epilepsy. Drug treatment is the major form of therapy for a vast majority of children with epilepsy. The choice of antiepileptic drugs (AEDs) in a child depends on the type of seizures, syndrome diagnosis, age of the patient and its consequent adverse effects. The metabolism of AED also differs according to the pediatric age group, requiring different dose regimens. Here, a brief review of AED used in the pediatric age group is presented.