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 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.
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D019826:Cholic Acid; D002793:Cholic Acids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D006000:Glycocholic Acid / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008148:Lovastatin / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D009865:Oocytes / Q000378:metabolism; D010590:Phalloidine / Q000494:pharmacology; D011355:Prodrugs; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013656:Taurocholic Acid / Q000378:metabolism; D014982:Xenopus laevis
D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D002793:Cholic Acids; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011355:Prodrugs; D011725:Pyridines; C038659:taurocholate carrier protein, rat; C062437:HR 780; D010590:Phalloidine; D013656:Taurocholic Acid; D008148:Lovastatin; D019826:Cholic Acid; D006000:Glycocholic Acid