Studies on the uptake of low molecular weight monomeric tris-galactosyl conjugates by the rat liver.

We have attempted to direct low molecular weight compounds to the liver via the internalizing asialoglycoprotein receptor on parenchymal cells by conjugation to a monomeric triantennary galactosyl cluster. Acetate and a hypolipidaemic ansamycin were derivatized and the biodistribution of the conjugates was determined 250 sec and 30 min after administration to Wistar rats. The ansamycin conjugate (CGH46) was rapidly cleared from the circulation by the liver; after 250 sec, 64% of the radiolabelled dose was found in the liver compared to 18% in the blood. However, the distribution of the conjugate did not differ significantly from that of unconjugated ansamycin (CGH45). Tris-galactosyl acetate showed no capacity to localize in the liver, with only 2% recovered from that organ 250 sec after administration compared to 38% in the blood and 13-18% in the kidneys, skin and muscle. Extraction efficiency of CGH46 by isolated perfused rat livers was almost 20% of the administered dose and this value was not significantly changed by co-administration of specific inhibitors of the uptake process. It is concluded that derivatization of low molecular weight molecules with monomeric triantennary galactosyl residues is unlikely to increase their affinity for the liver.

Hypolipidaemic activity of a novel acyclic ansamycin derivative. Synthesis and pharmacokinetic and pharmacodynamic studies in rodents.

Certain classes of the antibacterial agent rifamycin SV have recently been shown to possess marked hypolipidaemic activity. An acyclic oxazolylrifamycin has been prepared and its hypolipidaemic properties evaluated; it was found to be significantly more potent when administered orally to Wistar and Sprague-Dawley rats than other previously described rifamycin hypolipidaemics. The plasma decay rate of a bolus of intravenously administered 125I-LDL (low density lipoprotein) was significantly greater in treated rats than in rats receiving vehicle alone, compatible with a drug-induced increase in LDL catabolism. A bolus of radiolabelled drug was rapidly removed from the circulation by the liver, the presumed target organ. Compound 3 constitutes the first example of a new class of acyclic hypolipidaemic ansamycins.