Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs

Department of Pharmacy, Box 357630,University of Washington, Seattle, WA 98195, USA.
Neurology (Impact Factor: 8.29). 12/2004; 63(10 Suppl 4):S3-8. DOI: 10.1212/WNL.63.10_suppl_4.S3
Source: PubMed


One of the major differences between the older antiepileptic drugs (AEDs) and the newer AEDs is the potential of the older AEDs for significant interactions with other medications. Many of the drug-drug interactions involving the older AEDs are reciprocal, i.e., both drugs affect each other. In contrast, the newer AEDs have either no or limited drug interaction potential. Despite our extensive understanding of and our ability to predict drug-drug interactions, serious drug interactions still occur. More than 30% of all new seizures occur in the elderly, and because this population may be taking a variety of other medications the addition of an AED can have profound impact on these other therapies. In women, the use of enzyme-inducing AEDs can cause significant alterations of sex hormones and can decrease the efficacy of oral contraceptives. In children and adults, the use of enzyme inducers may result in long-term endocrine effects, including bone loss and lipid, thyroid, and sex hormone abnormalities. Phenytoin and phenobarbital are metabolized by cytochrome P450 isozymes, with activity dependent on genetic polymorphism (CYP2C9, CYP2C19). The dosing of the newer AEDs is not affected by genetic polymorphism. The decreased induction and inhibition effects and the lack of significant genetic polymorphism of the newer AEDs allow increased ease of use and perhaps greater safety, especially for patients taking multiple medications.

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    • "The expression and function of phase II enzymes in the human epileptic brain remains to be fully elucidated. Phase II conjugation enzymes (glutathione-S-transferases [GSTs], sulfotransferase, and UDP-glucuronosyl-transferase [UGTs]) are involved in the biotransformation of important AEDs, such as lamotrigine, which is a substrate of UGT1A4 (Anderson, 2004, 2008; Ghosh et al., 2012). It is unknown whether UGT1A4 is expressed in the drug-resistant human epileptic brain and whether this expression plays a role in drug metabolism. "
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    ABSTRACT: Brain drug bioavailability is regulated by the blood-brain barrier (BBB). It was recently suggested that cytochrome P450 (CYP) enzymes could act in concert with multidrug transporter proteins to regulate drug penetration and distribution into the diseased brain. The possibility that phase II metabolic enzymes could be expressed in the epileptic brain has been not evaluated. Phase II enzymes are involved in the metabolism of common antiepileptic drugs (AEDs). Phase II enzyme UGT1A4 brain expression was evaluated in temporal lobe resections from patients with epilepsy. UGT1A4 expression was determined by western blot and immunocytochemistry in primary cultures of human drug-resistant brain endothelial human brain epileptic endothelial cells (EPI-EC)s and commercially available control cells human brain microvascular endothelial cells (HBMECs). Lack of DNA condensation measured by 4',6-diamidino-2-phenylindole (DAPI) was used as a surrogate marker of cell viability and was correlated to UGT1A4 expression high performance liquid chromatography ultraviolet detection (HPLC-UV) was used to quantify lamotrigine metabolism by EPI-EC and HBMEC. The appearance of the specific lamotrigine metabolite, 2-n glucuronide (MET-1), was also evaluated. Lamotrigine and MET-1 levels were measured in selected surgical brain and matched blood samples. UGT1A4 expression was observed in BBB endothelial cells and neurons. Our quantification study revealed variable levels of UGT1A4 expression across the brain specimens analyzed. Neurons devoid of UGT1A4 expression displayed nuclear DAPI condensation, a sign of cellular distress. UGT1A4 overexpression in EPI-EC, as compared to HBMEC, was reflected by a proportional increase in lamotrigine metabolism. The lamotrigine metabolite, MET-1, was formed in vitro by EPI-EC and, to a lesser extent, by HBMEC. HPLC-UV measurements of brain and blood samples obtained from patients receiving lamotrigine prior to surgery revealed the presence of lamotrigine and its metabolites in the brain. These initial results suggest the presence of a phase II enzyme in the epileptic brain. Further studies are required to fully describe the pattern of brain UGT1A4 expression in relation to clinical variables and drug resistance.
    Epilepsia 07/2013; 54(9). DOI:10.1111/epi.12318 · 4.57 Impact Factor
    • "Carbamazepine pharmacokinetic data in epileptic patients[12345678910111213141516171819202122232425262728293031323334353637383940414243444546474849505152535455] "
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    ABSTRACT: Carbamazepine has been used as AEDs since 1965, and is most effective against partial seizures. Two basic mechanisms of action have been proposed: 1) enhancement of sodium channel inactivation by reducing high-frequency repetitive firing of action potentials, 2) and action on synaptic transmission. The aim of this study was to provide a review of carbamazepine pharmacokinetics and its management guidelines in Iranian epileptic population. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO), Web of Science were searched; 1600, 722 and 167 research and review articles relevant to the topics; carbamazepine pharmacokinetics, carbamazepine pharmacokinetics in epilepsy and review on carbamazepine pharmacokinetics in epilepsy were found, respectively. Carbamazepine is highly bound to plasma proteins. In patients the protein-bound fraction ranged from 75-80% of the total plasma concentration. Bioavailability ranges from 75-85%. The rate or extent of absorption was not be affected by food. It is completely metabolized and the main metabolite is carbamazepine-epoxide (CBZ-E). Carbamazepine induces its own metabolism, leading to increased clearance, shortened serum half-life, and progressive decrease in serum levels. Increases in daily dosage are necessary to maintain plasma concentration. Severe liver dysfunction may cause disordered pharmacokinetics. In cardiac failure, congestion of major vital organs, including kidneys, may result in abnormally slow absorption and metabolism. Carbamazepine shows variability due to its narrow therapeutic window. Therefore clinical management in a3n Iranian epileptic population should focus on results derived from therapeutic drug monitoring in order to reduce inter and intra- individual variability in plasma drug concentrations.
    Journal of research in medical sciences 03/2013; 18(Suppl 1):S81-5. · 0.65 Impact Factor
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    • "A pharmacological interaction occurs when one drug modifies the activity of another, increasing or reducing its effects [37,87]. Pharmacokinetic interactions occur when one drug interferes with the distribution in the organism of another drug, altering its concentration at the site of action. "
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    ABSTRACT: In patients with brain tumor (BT), seizures are the onset symptom in 20-40% of patients, while a further 20-45% of patients will present them during the course of the disease. These patients present a complex therapeutic profile and require a unique and multidisciplinary approach. The choice of antiepileptic drugs is challenging for this particular patient population because brain tumor-related epilepsy (BTRE) is often drug-resistant, has a strong impact on the quality of life and weighs heavily on public health expenditures. In BT patients, the presence of epilepsy is considered the most important risk factor for long-term disability. For this reason, the problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control can significantly improve the patient’s psychological and relational sphere. In these patients, new generation drugs such as gabapentin, lacosamide, levetiracetam, oxcarbazepine, pregabalin, topiramate, zonisamide are preferred because they have fewer drug interactions and cause fewer side effects. Among the recently marketed drugs, lacosamide has demonstrated promising results and should be considered a possible treatment option. Therefore, it is necessary to develop a customized treatment plan for each individual patient with BTRE. This requires a vision of patient management concerned not only with medical therapies (pharmacological, surgical, radiological, etc.) but also with emotional and psychological support for the individual as well as his or her family throughout all stages of the illness.
    DNA research: an international journal for rapid publication of reports on genes and genomes 06/2012; 10(2):124-33. DOI:10.2174/157015912800604470 · 3.05 Impact Factor
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