COMPARATIVE PHARMACOKINETICS OF THE NEWER ANTIEPILEPTIC DRUGS

During the past few years a major increase has taken place in the numb er of drugs which have become available in the antiepileptic arsenal. In fact, 3 new antiepileptic drugs, vigabatrin. oxcarbazepine and lamo trigine, were recently approved in several European countries. Two oth er drugs, felbamate and gabapentin, are expected to be approved in the US in the near future. This review comparatively evaluates the pharma cokinetics of the following 10 new antiepileptic drugs: felbamate, flu narizine, gabapentin, lamotrigine, oxcarbazepine, remacemide, stiripen tol, tiagabine, topiramate and vigabatrin. Three of the new drugs, gab apentin, topiramate and vigabatrin, are more promising on the basis of their pharmacokinetic features. They are well absorbed, excreted main ly unchanged in the urine, and are not susceptible to enzyme induction or inhibition. Their drug interaction potential appears to be minimal . About 50% of felbamate is excreted unchanged, with the rest eliminat ed by metabolism. The remaining drugs are eliminated by metabolic proc esses such as glucuronidation (lamotrigine), deglycine formation (rema cemide) or oxidative metabolism (flunarizine and stiripentol). Oxcarba zepine and remacemide have high hepatic clearance and are biotransform ed to hydroxy and deglycine metabolites, respectively, with the activi ty of their metabolites contributing to the antiepileptic activity of the parent drug after oral administration, despite high first-pass eff ect metabolism. Gabapentin and oxcarbazepine do not behave pharmacokin etically as their original design intended. Gabapentin is not effectiv e as a chemical drug delivery system for gamma-aminobutyric acid (GABA ), and oxcarbazepine serves as a prodrug to its hydroxy metabolite, bu t does not act as a drug on its own. Nevertheless, these 2 agents demo nstrate efficacy in extensive preclinical and clinical trials. Althoug h the pharmacokinetics features of these drugs are important, these fe atures are secondary to their pharmacodynamic properties - i.e. to the requirement that new antiepileptic drugs have to have proven clinical efficacy and safety in epileptic patients.