Interactions of antiepileptic and psychotropic drugs –pharmacogenetics of cyp enzymes and p-glycoprotein transporter

Antiepileptics (AEs) and psychotropic drugs are increasingly used in combination, which makes the possibility of drug interactions between them feasible. Most pharmacokinetic interactions between AEs and psychoactive drugs occur at a metabolic level, and involve changes in the activity of the Cytochrome P-450(CYP) metabolic enzymes and on the level of transporter proteins, primarily P-glycoprotein (P-gp) and multi-drug resistance protein (MRP). Not only inter-individual but also significant inter-ethnic differences exist in the frequency of polymorphic variant of genes that determine the activity of CYP and P-gp. Genetic predisposition determines not only efficacy and toxicity of the single drug but also modulates the extent of drug interaction. CYP enzymes involved in the metabolism of AE and psychotropic drugs include CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Some AE and psychotropic drugs are also inhibitors or inducers of the CYPs and P-gp. As a consequences of CYP induction or inhibition, plasma concentrations of a given drug may reach toxic or subtherapeutic levels, and dosage adjustments may be required. Enzyme-inducing AED such as carbamazepine, phenytoin and barbiturates, stimulate the oxidative biotransformation of many psychotropic drugs. In particular, they may decrease the plasma concentrations of tricyclic antidepressants, haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, quetiapine and some benzodiazepines. Psychotropic drugs such as nortriptyline, fluoxetine, fluvoxamine, sertraline, haloperidol may lead to higher serum levels of carbamazepine, phenytoin and lamotrigine. Pharmacogenetic analysis of polymorphic variants of CYP and P-gp may contribute to therapy individualization because it is possible to predict transporter and metabolic capacity for a certain drug on the basis of the patient’s genotype.