Pharmacokinetics and pharmacodynamics of valproate analogs in rats. III. Pharmacokinetics of valproic acid, cyclohexanecarboxylic acid, and 1-methyl- 1-cyclohexanecarboxylic acid in the bile-exteriorized rat

The pharmacokinetics of valproic acid (VPA) and its structural analogs cyclohexanecarboxylic acid (CCA) and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) were examined in bile-exteriorized rats. A 0.52 mmol/kg dose (equivalent to 75 mg/kg VPA) of test compound (N = 4 rats per compound) was administered as an intravenous bolus. VPA, CCA, and MCCA concentrations in serum, bile, and urine were determined by gas chromatography before and after incubation in sodium hydroxide to hydrolyze base-labile conjugates. Concentration-time profiles of these compounds in serum displayed apparent Michaelis-Menten kinetics. Serum concentrations of base-labile conjugates were similar to parent concentrations for VPA, were an order of magnitude lower than parent concentrations for CCA, and were undetectable for MCCA. Urinary recovery of base-labile (apparently glucuronide) conjugates in the bile-exteriorized rat was 28.8%, 12.0%, and 25.2% of the administered dose for VPA, CCA, and MCCA, respectively. In contrast, more than 50% of the dose for VPA and MCCA was recovered in bile as the base-labile conjugate, with less than 5% of the CCA dose recovered via this excretory route. Bile flow was stimulated significantly by VPA and MCCA, but not by CCA; changes in bile flow correlated with the biliary excretion rate of base-labile conjugates rather than with excretion of the parent compounds themselves. These data suggest that (1) the disposition of low molecular weight monocarboxylic acids is generally nonlinear, (2) hepatic conjugation of these compounds may be favored by the presence of a branched chain at the α-carbon, and (3) choleresis occurs when biliary excretion of base-labile conjugate is a quantitatively significant route of elimination.