Pharmacokinetic properties of ethosuximide in monkeys. I. Single-dose intravenous and oral administration.

Abstract

The pharmacokinetic profile of ethosuximide was studied in 6 chronically catheterized male rhesus monkeys at three dose levels (30, 60, and 90 mg/kg), intravenously and orally. Plasma and urine levels were assayed by GLC. The intravenous and oral kinetics of ethosuximide were described in terms of a one-compartment open model with first-order elimination (and first-order absorption for oral kinetics). Volume of distribution (overall mean +/- SD=0.80 +/- 0.09 liters/kg), total body clearance (overall mean +/- SD= 19.2 +/- 2.70 ml/hr/kg) and elimination half-life (overall mean +/- SD=28.98+/-3.35 hr and 28.10+/-3.17 hr following intravenous and oral administration, respectively) remained constant over the dosage range Appendix) was selected to describe the disposition of ethosuximide in monkeys. Accordingly, plasma concentrations of individual animals and the average concentrations of Fig. 1 were fitted to a monoexponential equation [Eq. (A1)]. A close agreement between experimental datum points and least-squares fit lines was observed at all three dose levels. Plots of C0 and area under the plasma concentration-time curve [AUC, measured by trapezoidal rule, Eq. (A3)] vs dose (Fig. 4) were linear as predicted by Model I. It may be concluded, therefore, that a one-compartment open model with first-order elimination is appropriate to describe the intravenous kinetic behavior of ethosuximide in monkeys. The volume of distribution (overall mean +/- SD = 0.80 +/- 0.09 liters/kg) observed in the present study is higher than total body water and therefore suggests accumulation of ethosuximide in body tissues. Tissue distribution studies have not been performed in monkeys. However, data on tissue/plasma ratios in rats (Dill et al., 1965; Chang et al., 1972) indicate that ethosuximide can partition outside the total body water compartment. This behavior is compatible with the high pKa value and negligible protein-binding characteristics of ethosuximide (Chang et al., 1972). As discussed by several workers (Levy, 1968; DiSanto and Wagner, 1972; Lockard et al., 1974), the establishment of dose independency in elimination processes (kinetic linearity) requires that single-dose studies be performed at several dose levels. In the dose range examined in the present study (30 to 90 mg/kg), there was no evidence of dose-dependent elimination kinetics after intravenous or oral administration. The overall mean (+/- SD) elimination half-life (28.5 +/- 3.24 hr) obtained in the present study is somewhat longer than the value (22.0 hr) observed by Chang et al. (1972) following a single-dose (100 mg/kg) oral administration of ethosuximide in 4 rhesus monkeys. In view of the agreement between the predictions of Model I and experimental intravenous data, a one-compartment open model with first-order absorption and elimination processes (Model II, Appendix) was studied. The bioavailability of the syrup formulation used in the oral studies was essentially complete (overall mean +/- SD=96% +/- 12.0) and dose-independent...