An osmotic explanation for valproic acid induced choleresis in the rat, dog and monkey

I.v. administration of sodium valproate (NaVPA), the sodium salt of 2-n-propylpentanoic acid (valproic acid, VPA, Depakene®), to rats and dogs caused an immediate stimulation of bile flow, the magnitude and duration of which was dependent on the dose. In rats given ¹⁴C-erythritol, a linear relationship between biliary clearance of erythritol and bile flow indicated that the choleresis was canalicular, rather than ductular, in origin. Increased bile flow was not mediated through an enhanced output of bile acids. Bile produced during choleresis was lower in choleride and bicarbonate concentrations than equivalent bile from control rats given only saline i.v. This anion gap was more than compensated by the amount of VPA-glucuronide (anionic at physiological pH values) in the bile. A close linear relationship existed between the volume of additional bile produced and the amount of conjugated VPA excreted in the bile. The results support the hypothesis that VPA induces choleresis by the osmotic effects of transport of its metabolites across the canalicular membrane.