Disposition of progabide and valproic acid following intraperitoneal administration in rhesus monkey

The pharmacokinetic characteristics of progabide, a new gamma-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 (t 1/2) 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 t 1/2 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.(ABSTRACT TRUNCATED AT 250 WORDS)