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Disposition of Progabide and Valproic Acid Following Intraperitoneal Administration in Rhesus Monkey

Summary: The pharmacokinetic characteristics of progabide, a new γ‐aminobutyric acid‐mimetic drug, were evaluated following single‐ and multiple‐dose administration of a progabide suspension through a chronic intraperitoneal catheter. Several issues pertaining to the bioavailability of progabide were addressed: first‐pass effect, incomplete dissolution, and dose and time dependency. Four male monkeys received five treatments: three intraperitoneal doses (50, 100, and 150 mg), one oral dose (50 mg), and one intravenous bolus dose (150 mg). Bioavailability following intraperitoneal administration was incomplete, consistent with a first‐pass effect predicted from intravenous data. There were no significant differences between the absolute bioavailabilities of the three intraperitoneal doses, which ranged between 40 and 49%. The apparent half‐life (t1/2) observed after intraperitoneal administration was significantly longer than the elimination half‐life by the intravenous route and tended to increase with dose. This behavior is consistent with dissolution rate‐limited absorption. The bioavailability of the suspension administered orally was compared with that of the intraperitoneal route, and no difference was found. However, the apparent t1/2 by the oral route was significantly longer than that of the intraperitoneal route. In multiple‐dosing studies, four different dosing regimens (all intraperitoneal) were examined, including 50 mg every 2 or every 6 h, 20 mg every 2 h, and 40 mg every 4 h. In all these regimens, plasma levels exhibited an accumulation compared with single‐dose predictions. Large oscillations in plasma levels were observed when the dosing interval was 6 h and side effects were observed when the dosing interval was 2 h. A dosing regimen of 40 mg every 4 h was optimal. The pharmacokinetics of valproic acid after intraperitoneal administration were also examined. Valporate exhibited complete bioavailability (93% as a mean value) by the intraperitoneal route, and no accumulation was observed during multiple dosing.