MECHANISM OF KETOCONAZOLE-INDUCED ELEVATION OF INDIVIDUAL SERUM BILE-ACIDS IN THE RAT - RELATIONSHIP TO THE EFFECT OF KETOCONAZOLE ON BILE-ACID UPTAKE BY ISOLATED HEPATOCYTES

Ketoconazole, an imidazole derivative, has been implicated in a number of hepatic dysfunctions. The aim of the present study was to determin e the effect of in vivo treatment of rats with ketoconazole on individ ual serum bile acid levels and the in vitro effects of ketoconazole on the hepatocellular uptake of two bile acids and two other model subst rates transported by liver cells. Male Sprague-Dawley rats were treate d i.p, with a single injection of ketoconazole of 25 mg/kg (n = 4) or 50 mg/kg (n = 4); the control group (n = 4) received the vehicle only at a dose of 1 ml/kg. Blood samples were collected at 4 hr after dosin g. With high-performance liquid chromatography, the serum was assayed for individual serum bile acids. At the higher dose, ketoconazole prod uced a significant increase in serum levels of cholic acid, taurocholi c acid, chenodeoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid and taurochenodeoxychol ic acid compared with the control group (P<.05). Cholic acid, taurocho lic acid and chenodeoxycholic acid levels were significantly raised in rats treated with the lower dose. In vitro, ketoconazole strongly inh ibited the hepatocellular uptake of [C-14]cholic acid, [C-14]taurochol ic acid and [H-3]ouabain but not [C-14]2-aminoisobutyric acid, which i ndicated that the effect is relatively specific. The kinetics of inhib ition were competitive and the inhibition constants for taurocholate a nd ouabain were 6 and 1 mu M, respectively. Ketoconazole inhibited bot h Na+-dependent and Na+-independent taurocholate uptake and stimulated bile acid countertransport of preloaded hepatocytes. The data suggest that the rise in the serum levels of cholic and taurocholic acids aft er ketoconazole treatment in rats is mainly related to the inhibitory effect induced by this drug on the hepatocellular uptake of these bile acids. The effect is specific and could help to explain the mechanism by which ketoconazole induces its hepatic dysfunction.