CLINICALLY SIGNIFICANT PHARMACOKINETIC DRUG-INTERACTIONS WITH CARBAMAZEPINE - AN UPDATE

Carbamazepine is one of the most commonly prescribed antiepileptic dru gs and is also used in the treatment of trigeminal neuralgia and psych iatric disorders, particularly bipolar depression. Because of its wide spread and long term use, carbamazepine is frequently prescribed in co mbination with ether drugs, leading to the possibility of drug interac tions. The most important interactions affecting carbamazepine pharmac okinetics are those resulting in induction or inhibition of its metabo lism Phenytoin, phenobarbital (phenobarbitone) and primidone accelerat e the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concentrations to a c linically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concentrations can be caused by stiripentol, remacemide, acetazolamide, macrolide an tibiotics, isoniazid, metronidazole, certain antidepressants, verapami l, diltiazem, cimetidine, danazol and (dextropropoxyphene) propoxyphen e. In other cases, toxic symptoms may result from elevated plasma conc entrations of the active metabolite carbamazepine-10,11-epoxide, due t o the inhibition of epoxide hydrolase by valproic acid (sodium valproa te), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also increase glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonv ulsants, particularly valproic acid, clonazepam, ethosuximide, lamotri gine, topiramate, tiagabine and remacemide. The metabolism of many oth er drugs such as tricyclic antidepressants, antipsychotics, steroid or al contraceptives, glucocorticoids, oral anticoagulants, Cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can als o be induced, leading to a number of clinically relevant drug interact ions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particul arly with respect to its therapeutic index, site of metabolism and abi lity to affect specific drug metabolising isoenzymes. Avoidance of unn ecessary polypharmacy, selection of alternative agents with lower inte raction potential, and careful dosage adjustments based on serum drug concentration monitoring and clinical observation represent the mainst ays for the minimisation of risks associated with these interactions.