Disposition of valproic acid in patients with liver disease

Summary

The disposition of valproic acid (di-n-propylacetate; VA) has been studied after a single oral dose of a solution of 450 mg in 7 patients with alcoholic cirrhosis and in 4 patients recovering from acute hepatitis. The diagnosis was based on biochemical function tests and histological findings. The pharmacokinetic parameters were compared with those reported for healthy volunteers. VA in therapeutic concentration (80 µg/ml) in plasma was less bound to plasma proteins in patients with alcoholic cirrhosis (70.7±11.3%) and in patients recovering from acute hepatitis (78.1±14.1%) than in controls (88.7±5.2%). The reduced binding affected the blood/plasma concentration ratio and the apparent distribution volume Vd_(β); the latter was increased from the normal value of 0.14±0.05 l/kg to 0.22±0.09 (p<0.05) in alcoholic cirrhotics, and to 0.20±0.07 (p=0.056) in patients recovering from acute hepatitis. The half-life of elimination T_{1/2 (β)} (controls=12.2±3.7 h) was significantly (p<0.05) prolonged in cirrhotics (18.9±5.1 h) and in patients recovering from acute hepatitis (17.0±3.7 h). The plasma$\overline {Cl}$ of total drug was not impaired, which can best be explained by the lower plasma protein binding, which might have increased the$\overline {Cl}$ of this drug which shows restricted clearance. In addition, the plasma$\overline {Cl}$ of free drug was significantly (p<0.02) reduced in alcoholic cirrhotics. During a two day urine collection no measurable amount of unchanged VA was recovered. There was considerable excretion of VA-conjugates, which could be hydrolyzed either by HCl or by β-glucuronidase/arylsulphatase (4–23% of the dose). These percentages were in the same range as in normals (26.7±16.1%). The study indicates that elimination of VA is slightly impaired in patients with dysfunction of the liver.