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

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 with the bile acids cholic acid, taurocholic acid, and glycocholic acid. Hepatic uptake 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 drug excretion. The experiments showed that the parent drug HR 780 was slowly excreted into bile. In contrast, the excretion of the bile acid-conjugated HR 780 derivatives S 3554 (conjugated with cholate), S 3898 (conjugated with glycocholate), and S 4193 (conjugated with taurocholate) was rapid and very efficient in both groups of rat strains. The bile acid-conjugated HMG-CoA reductase inhibitors showed a 10 to 20 times higher affinity for the uptake systems of bile acids than the noncoupled parent drug compounds, and even higher affinities than the bile acids 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 (Ki = 1 mumol/L). Uptake of radiolabeled S 3554 into isolated rat hepatocytes was observed to be rapid, cell specific, saturable, energy dependent, and carrier mediated. However, the carrier for S 3554 uptake was found not to be the cloned Na(+)-dependent taurocholate cotransporting polypeptide Ntcp. Expression of this carrier cRNA in Xenopus laevis oocytes did not stimulate S 3554 uptake.

Drug transporters in pharmacokinetics

“…OATP carriers transport bile acids (Trauner and Boyer 2003) and a plethora of drugs (Hagenbuch and Meier 2003) including HMG-CoA reductase inhibitors such as pravastatin (Ziegler and Stünkel 1992;Ziegler and Hummelsiep 1993;Hsiang et al 1999). Oatps were addressed by drugs conjugated with bile acids in a bile acid-based drug targeting approach for the liver (Kramer et al 1992;Meijer 1993;Petzinger et al 1995;Kramer and Wess 1996).…”

Exploitation of Bile Acid Transport Systems in Prodrug Design

“…Compared to the parent drug the conjugates showed increased affinity for the hepatocyte bile acid transport systems. Alike behavior was observed for the intestinal transport system in brush border membrane vesicles [8,117,121]. Secretion profile similar to natural bile acids was detected contrary to the parent drug itself.…”

Synthesis and in vitro evaluation of potential sustained release prodrugs via targeting ASBT

“…Several bile acid conjugates were previously designed to provide site-directed liver and gallbladder delivery (Kramer et al, 1994; Kramer et al, 1992; Petzinger et al, 1995; Petzinger et al, 1999). For example, bile acid conjugates of a HMG-CoA reductase inhibitor were active against HMG-CoA reductase in rat liver after an oral administration (Kramer et al, 1994).…”