Valproic acid increases biliary copper excretion in the rat

The effect of valproic acid (VPA) on the copper absorption and disposition in rat small intestine was investigated using an in situ recirculating perfusion method. Following addition of VPA (20 mg) to the perfusion of 30 ml of 0.9% sodium chloride solution (2 μg/ml copper as CuSO₄) there were no significant differences in copper decline during the perfusion. The absorption rate constant of copper (k_a) which was estimated from the copper decline in the perfusion was unchanged without and with VPA (0.19±0.02 vs. 0.17±0.03 1/h). These results indicate that VPA does not have an effect on copper absorption from the intestine. We also assessed biliary copper excretion by measuring bile flow and biliary copper concentrations. Addition of VPA markedly increased bile flow by 47% for the first hour of bile collection and 91% for the second hour and the biliary copper excretion closely followed the increase in bile flow (without VPA: 0.93±0.15 vs. with VPA: 1.44±0.21 mg for the first and without VPA: 0.98±0.13 mg vs. with VPA: 1.98±0.22 mg for the second hour of bile collection). The total mean value for the biliary copper excretion was increased by 79%. The serum VPA concentration after the perfusion was 31.1±3.2 μg/ml. This high excretion of copper induced by VPA into the bile may upset the homeostatic balance of copper and cause the abnormalities of serum copper concentration. Based on the present studies, we should pay attention to copper levels in patients with VPA treatment.