HEPATOBILIARY TRANSPORT OF HEPATIC 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITORS CONJUGATED WITH BILE-ACIDS

To obtain prodrugs with affinity to Liver parenchymal cells, the hepat ic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor s HR 780 and lovastatin (syn. mevinolin) were conjugated with the bile acids cholic acid, taurocholic acid, and glycocholic acid. Hepatic up take and biliary excretion of the coupled drugs were investigated and compared with the noncoupled drugs, Studies were performed with livers of normal Wistar rats, and TR(-)/GT(-) Wistar rats with deficient dru g excretion. The experiments showed that the parent drug HR 780 was sl owly excreted into bile. In contrast, the excretion of the bile acid-c onjugated HR 780 derivatives S 3554 (conjugated with cholate), S 3898 (conjugated with glycocholate), and S 4193 (conjugated with taurochola te) was rapid and very efficient in both groups of rat strains. The bi le acid-conjugated HMG-CoA reductase inhibitors showed a 10 to 20 time s higher affinity for the uptake systems of bile acids than the noncou pled parent drug compounds, and even higher affinities than the bile a cids themselves. The cholate conjugate of HR 780 (compound S 3554) was shown. to be a noncompetitive inhibitor of taurocholate uptake and a competitive inhibitor of sodium-independent cholate uptake (K-i = 1 mu mol/L). Uptake of radiolabeled S 3554 into isolated rat hepatocytes w as observed to be rapid, cell specific, saturable, energy dependent, a nd carrier mediated. However, the carrier for S 3554 uptake was found not to be the cloned Na+-dependent taurocholate cotransporting polypep tide Ntcp. Expression of this carrier cRNA in Xenopus laevis oocytes d id not stimulate S 3554 uptake.