The concentrations of amitriptyline (AMT) and its demethylated metabolite nortriptyline (NRT) in the serum and in specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of AMT in rats. Both AMT and NRT declined from the serum in a biexponential manner and were eliminated monoexponentially from the brain regions, with no significant difference in elimination among the eight brain regions examined. In the brain, both AMT and NRT were unevenly distributed after chronic administration, whereas an even distribution was observed after acute administration. The AUCbrain:AUCserum ratio of AMT was higher than that of NRT, indicating greater transport of AMT into the brain regions. The AUCAMT value in the serum increased 1.6 times after chronic administration, whereas no significant changes were observed in the brain regions. The AUCNRT values increased 9.0 times in the serum and 6.8 times in the brain, with the increase in the serum being greater. These results suggest inhibited distribution of the drugs into the tissues, including the brain regions, and enhanced metabolism of AMT.

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The effects of zonisamide (ZNS) on the pharmacokinetics of phenobarbital (PB), valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) were investigated in rats. Additionally, the influence of ZNS on the serum protein binding, erythrocyte distribution and metabolism of these antiepileptics was studied in vitro. The t 1/2 and AUC values of PB were significantly increased by ZNS coadministration, and a significant decrease in the Vd/F value of PHT was observed after multiple dosing of ZNS. By contrast, ZNS showed no significant effect on VPA and CBZ kinetics. No significant effect of ZNS was observed in the serum protein binding, erythrocyte distribution or metabolism of other antiepileptics. These results suggest that ZNS has little effect on the pharmacokinetic behaviors of other antiepileptic drugs.

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