Pharmacokinetic Properties of Ethosuximide in Monkeys. I. Single‐Dose Intravenous and Oral Administration

SUMMARY 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 f SD ≟ 19.2 ±2.70 ml/hr/kg) and elimination half‐life (overall mean k SD = 28.98 * 3.35 hr and 28.10 f 3.17 hr following intravenous and oral administration, respectively) remained constant over the dosage range suximide 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 (f SD) elimination half‐life (28.5 f 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 onecompartment open model with first‐order absorption and elimination processes (Model 11, Appendix) was studied. The bioavailability of the syrup formulation used in the oral studies was essentially complete (overall mean ? SD = 96% k 12.0) and dqse‐independent. The fraction of dose excreted unchanged in urine (overall mean k SD) was 0.32 ± 0.07. RÉSUMÉ Le profil pharmacocin6tique de l'ethosuximide a ht6 htudih chez 6 singes mdles Rhesus munis de catheters permanents aux trois doses de 30, 60, et 90 mg/kg par voies intraveineuse et orale. Les concentrations plasmatiques et urinaires ont ht6 mesurCes par chromatographie gaz‐liquide. Les cinktiques orale et intraveineuse ont 6 th rapportkes 1 un modde ouvert 1 un compartiment avec une Blimination d'ordre 1 (et une absorption d'ordre 1 pour la cinhtique orale). Le volume de distribution (moyenne f kart‐type ≟ 0.80 f 0.09 L/kg), la clearance corporelle totale (moyenne f Bcart‐type ≟ 9.2 f 2.70 ml/hr/kg) et la demi‐vie d'elimination (moyenne f karttype = 28.98 f 3.35 hr et 28.10 f 3.17 hr, apr6s administration intraveineuse et orale, respectivement) sont rest& constants pour les doses étudieQ. La biodisponibilit6 de la forme sirop utilisBe dans les etudes par voie orale Btait es sentiellement complMe (moyenne f Bcart‐type = 96%± 12.0) et independante de la dose. La fraction de la dose excr6tBe inchangC dans l'urine (moyenne f hart‐type) Btait de 0.32 ± 0.07 RESUMEN Se ha estudiado el perfil farmacodinamico de la etosuximida en tres dosis a niveles distintos (30, 60, y 90 mg/kg) administradas oral e intravenosamente a 6 monos rhesus machos cateterizados. Los niveles de orina y plasma se determinaron mediante cromatograffa de gas‐liquido. La dinamica oral e intravenosa de la etosuximida se ha descrito en terminos de un modelo de compartimiento abierto con elimina‐cion de primer orden (y absorcion de primer orden para la dinamica oral). El volumen de distribution (promedio general ± SD ≟ 0.80 ± 0.0.9 L/kg), el aclaramiento corporal total (promedio general ± SD ≟ 19.2 ± 2.70 ml/hr/kg) y la vida media de eliminacidn (promedio general ± SD ≟ 28.98 ± 3.35 horas y 28.10 ± 3.17 horas, tras la administration intravenosa u oral respectivamente), permanecieron constantes en los margenes de dosis estudiadas. La biodisponi‐bilidad de la formula usada en el jarabe utili‐zado fue esencialmente completa (promedio global ± SD = 96%± 12.0) e independiente de la dosis. La fraccidn de la dosis excretada sin modificar en la orina (promedio global ± SD) fu6 de 0.32 ± 0.07. ZUSAMMENFASSUNG Das pharmakokinetische Profil von Etho‐suximid nach intravenoser und oraler Vera‐breichung wurde an sechs chronisch katheteri‐sierten mannlichen Rhesusaffen untersucht. Die Dosierung war 30, 60, 90 mg/kg. Die Plasma‐und Urinkonzentrationen wurden mit GLC bestimmt. Die Kinetik von Ethosuximid nach oraler oder intravenoser Verabreichung wurde durch ein Modell mit einem offenen Komparti‐ment beschrieben. Verteilungsvolumen (Durchschnitt ± SD ≟ 0.80 ± 0.09 L/kg), Gesamtclearance (Durchschnitt ± SD ≟ 19.2 ± 2.70 mg/h/kg) und Halbwertszeit nach intravenoser bzw. oraler Verordnung waren konstant für die gesamte Dosisbreite. Die biologische Verfugbarkeit des sirupartigen Praparates, das bei der Untersuchung mit oralen Gaben benutzt wurde, war nahezu vollstandig (Durchschnitt ±SD = 96%± 12.0) und nicht dosisabhangig. Der Anteil der im Urin ausgeschiedenen nicht metabolisierten Menge (Durchschnitt ± SD) war 0.32 ±0.07.