Hepatobiliary transport of hepatic 3‐hydroxy‐3‐methylglutaryl coenzyme a reductase inhibitors conjugated with bile acids

摘要: Abstract To obtain prodrugs with affinity to liver parenchymal cells, the hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors HR 780 and lovastatin (syn. mevinolin) were conjugated bile acids cholic acid, taurocholic glycocholic acid. Hepatic uptake biliary excretion of coupled drugs investigated compared noncoupled drugs. Studies performed livers normal Wistar rats, TR − /GT rats deficient drug excretion. The experiments showed that parent was slowly excreted into bile. In contrast, acid-conjugated derivatives S 3554 (conjugated cholate), 3898 glycocholate), 4193 taurocholate) rapid very efficient in both groups rat strains. HMG-CoA a 10 20 times higher for systems than compounds, even affinities themselves. cholate conjugate (compound 3554) shown be noncompetitive inhibitor taurocholate competitive sodium-independent (K 1 = μmol/L). Uptake radiolabeled isolated hepatocytes observed rapid, cell specific, saturable, energy dependent, carrier mediated. However, found not cloned Na + -dependent cotransporting polypeptide Ntcp. Expression this cRNA Xenopus laevis oocytes did stimulate uptake.