Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs
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.
[Show abstract] [Hide abstract] ABSTRACT: Purpose: Dolutegravir (DTG) is primarily metabolized by UGT1A1 with CYP3A as a minor route. Carbamazepine (CBZ) is a potent inducer of these enzymes; thus, the effect of oral extended-release CBZ on DTG pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered. Methods: This was a single-center, open-label, fixed-sequence, crossover study in healthy adults. Subjects received three treatments: DTG 50 mg every 24 h (q24h) × 5 days in period 1, followed by CBZ 100 mg every 12 h (q12h) × 3 days, then 200 mg q12h × 3 days, then 300 mg q12h × 10 days in period 2, and DTG 50 mg q24h + CBZ 300 mg q12h × 5 days in period 3. No washout intervals occurred. Each dose was administered with a moderate-fat meal. Serial PK samples for DTG were collected on day 5 of periods 1 and 3. Plasma DTG PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90 % confidence intervals (CIs) were generated by the mixed-effect model for within-subject treatment comparisons. Safety assessments were performed throughout the study. Results: Sixteen subjects enrolled; 14 completed the study. CBZ significantly reduced DTG exposure: GMRs (90 % CI) for DTG + CBZ versus DTG alone were 0.51 (0.48-0.549), 0.67 (0.61-0.73), and 0.27 (0.24-0.31) for area under the curve from time zero to the end of the dosing interval (AUC(0-τ)), maximum observed plasma concentration (Cmax), and plasma concentration at the end of the dosing interval (Cτ), respectively. DTG alone and co-administered with CBZ was well tolerated. Conclusion: Integrase strand transfer inhibitor-naive subjects taking CBZ should receive DTG 50 mg twice daily versus once daily, as is recommended with other potent UGT1A/CYP3A inducers. ClinicalTrials.gov: NCT01967771.
- "In INI-resistant subjects, where the exposures of the higher 50 mg twice-daily regimen are required for antiviral activity against resistant virus, co-administration with these strong enzyme inducers should be avoided . Antiepileptic drugs are a diverse group of pharmacological agents and can generally be classified into two groups based on enzyme induction potential: enzyme-inducing and noninducing AEDs  . Although unstudied, the enzymeinducing AEDs such as phenytoin, oxcarbazepine, and1 Mean ± SD concentrationtime profile for dolutegravir (DTG) with and without concomitant administration of carbamazepine (CBZ). "
[Show abstract] [Hide abstract] ABSTRACT: Various dietary components, biological supplements might influence the incidence or management of epilepsy. Some studies reported that the supplementation with individual nutrients reduced seizure occurrence or improved other facets of health in epileptic patients. The beneficial dietary involvement identifying and avoiding allergenic foods, and avoiding suspected causing agents such as alcohol, aspartame, and monosodium glutamate. The Atkins diet (very low in carbohydrates) is a less preventive type diet that may be effective in some cases. Nutrients that may lessen seizure occurrence include vitamin B6, magnesium, vitamin E, manganese, taurine, dimethylglycine, and omega-3 fatty acids. Use of thiamine or vitamin B1 may improve cognitive function in epileptic patients. Supplementation with folic acid, vitamin B6, biotin or viatamine H, vitamin D, and L-carnitine may be needed to prevent or treat deficiencies resulting from the use of antiepileptic drugs. Vitamin K1 is recommended near the end of pregnancy for women taking antiepileptic drugs. Melatonin may reduce seizure occurrence in some cases, and progesterone may be useful for women with cyclic exacerbations of seizures. In the majority of cases, nutritional therapy is not a substitute for antiepileptic drugs. In some cases, depending on the effectiveness of the involvement, dosage reduction or discontinuation of drugs may be possible. However, nutrient supplementation may be necessary to prevent or reverse the effects of certain deficiencies that regularly result from the use of antiepileptic drugs.
- "Few studies have showed the effects of various foods on different hepatic enzymes (Hidaka et al., 2004Hidaka et al., , 2005 Kim et al., 2006; Hewitt et al., 2007). These foods might potentially affect the plasma levels of AEDs metabolized by hepatic enzymes, which may lead to either drug toxicity or inefficacy (Patsalos et al., 2002; Anderson, 2004). Future studies investigating the interactions between foods and cytochrome P450 enzymes are necessary to determine whether inhibition or induction of these enzymes activity by foods is clinically relevant. "
- "So in some cases, the chronic administration of the drug itself could be the solution to the problem rather than drug withdrawal. PHT has inductive properties (concentration-dependant) not only on enzymes but also on efflux transporters232425. This efflux transporter overexpression in the liver (biliary canaliculi) deviates PHT metabolism from a region (hepatocytes) with high content of CYP2C9/CYP2C19 (enzymes responsible for PHT metabolism) to a region (enterocytes) with low content of these enzymes , resulting in a lower PHT metabolism and thus a lower arene-oxide production.Figure 4 shows PHT elimination rate (β) multiplied by the plasma concentration of the main metabolite produced during PHT metabolism. "