Nonlinear ethotoin kinetics

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Abstract
Healthy subjects (5) were given single 500-, 1500- and 2500-mg doses of ethotoin [an anticonvulsant] as 250-mg tablets at 7-day intervals. Plasma samples were collected for 49 h after dosing and were asayed by HPLC [high performance liquid chromatography] for ethotoin. The drug was more slowly absorbed after the 2 higher doses. There was a disproportionate increase in AUC [area under the plasma concentration time curve] in all subjects with the escalating doses. Individual subject data were fitted to a 1st-order model and 1 incorporating Michaelis-Menten elimination kinetics. Of the 15 data sets, 11 were best described by the nonlinear model. All subjects reported visual disturbances with the 2 higher doses, and 4 of 5 experienced dyscoordination of gait with the 2500-mg dose. The effects did not appear to be related to plasma ethotoin concentration.

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