Effects of Various Antiepileptic Drugs on Plasma Levels of Lamotrigine, a Novel Antiepileptic, in Rats

The pharmacokinetics of lamotrigine (LTG) and effects of carbamazepine (CBZ), valproic acid (VPA) and zonisamide (ZNS) on LTG kinetics were investigated in rats. LTG plasma levels were measured by high-performance liquid chromatography (HPLC). A single oral administration of LTG at 2.5-10 mg/kg showed linear disposition kinetics. In the pharmacokinetic parameters of LTG when combined with CBZ, the maximal plasma concentration (Cmax) and the area under the plasma concentration curve (AUC0-36) values were significantly lower and the time to maximal plasma concentration (Tmax) value was significantly higher than those in LTG alone. Furthermore, the Cmax and AUC0-36 values of LTG when pretreated with CBZ for 7 days were significantly lower than those from simultaneous treatment with CBZ. The Cmax and AUC0-36 values of LTG when combined with VPA were significantly lower than those for LTG alone. There was no significant difference in the Tmax or time of elimination half-life (t1/2) values of LTG between simultaneous and pretreatment with VPA. Of the pharmacokinetic parameters of LTG with ZNS combination, the Cmax value of LTG after long-term dosings of ZNS decreased significantly, whereas no significant change in Cmax was observed after the combined single administration of LTG and ZNS. Single and chronic ZNS treatment did not significantly affect the Tmax, t1/2 and AUC0-36 values of LTG. The LTG trough level was significantly reduced by CBZ administration, reached the bottom level at 6 days after starting CBZ administration, and recovered gradually after withdrawal of CBZ. These results suggest that CBZ, VPA and ZNS causes changes in the plasma LTG level. They also suggest that in therapy combining LTG with one of these antiepileptics, especially CBZ, the LTG concentration in plasma should be monitored carefully.