Valproic acid (WA) is an anticonvulsant agent which produced marked choleresis in the rat. Bile flow rate increased from 50 to 60 pl per min per kg to 120 to 145 p1 per min per kg immediately after i.v. injection of VPA (37.5 to 150 mg per kg; 2 ml per kg) in male Sprague-Dawley rats. The duration of maximal bile flow was dose-dependent and increased from 30 min (37.5 mg VPA per kg) to approximately 2 hr (150 mg VPA per kg). Choleresis diluted the biliary concentrations of bile acids, C1-, cholesterol, and phospholipids. VPA did not change the bile/plasma ratio for erythritol suggesting that the increased bile flow is of canalicular origin. VPA did not influence the excretion of bile acids or their osmotic activity, whereas bile salt-independent flow doubled in rats treated with 150 mg VPA per kg. The bile/plasma, bile/liver, and liver/plasma concentration ratios for VPA were 11.7, 1.6, and 7.3, respectively. Approximately 90% of VPA appearing in bile was biotransformed, primarily as a glucuronide. Bile flow correlated with VPA excretion; 16 pl of bile was produced per pmole VPA which suggests that choleresis is primarily due to the osmotic activity of VPA metabolites in bile. VPA enhanced the excretion of inorganic ions which may also contribute to choleresis. Biliary excretion of phenol-3,6-dibromophthalein disulfonate and ouabain was unaffected. Thus, VPA is an effective choleretic which stimulates bile salt-independent flow of canalicular origin largely as a consequence of the osmotic properties of VPA conjugates in bile.
Valproic acid [ (VPA) 2-n-propylpentanoic acid, di-npropylacetic acid] is used in treatment of petit mal seizures (1-4). VPA is a simple eight-carbon branched-chain fatty acid which is structurally unrelated to other antiepileptic drugs. Until recently, few serious side effects were reported. Mild liver injury was observed as a transient asymptomatic rise in serum levels of aspartate and alanine aminotransferases (5). However, liver dysfunction has been fatal in several patients (6)(7)(8)(9)(10)(11). The mechanism by which VPA causes hepatic damage is unknown.
A single i.v. injection of VPA in rats and monkeys caused a dose-dependent increase in bile flow (12)(13)(14). The mechanism for this choleretic effect is the subject of this report.
Methods
VPA was obtained from Abbott Laboratories (North Chicago, Ill.) and Saber Laboratories, Inc. (Morton Grove, Ill.); carboxyl I4C-VPA (4.67 mCi per mmole) and 3H-ouabain (14.4 Ci per mmole) were obtained from New England Nuclear (Boston, Mass.); 14C-erythritol (2.3 Ci