Hepatic disposition of cationic drugs bound to asialoorosomucoid: lack of coendocytosis and evidence for intrahepatic dissociation.
A combination of protein binding, liver clearance, subcellular distribution and cell separation experiments was employed to investigate the influence of binding of cationic drugs to asialoorosomucoid (ASOR) on their hepatic uptake and intrahepatic distribution. Two quaternary ammonium drugs, d-tubocurarine and N-methyldeptropine, were selected because of their marked differences in hepatic processing and binding to ASOR. In spite of an increase in protein binding of 560% for d-tubocurarine and 380% for N-methyldeptropine, perfusate clearance of both drugs in isolated perfused rat livers was not influenced by addition of 75 mg of ASOR. Absence of coendocytosis was indicated by subcellular distribution studies revealing no extra enrichment of quaternary ammonium drugs in lysosomal fractions compared with control studies. Isolation of parenchymal and sinusoidal liver cells demonstrated d-tubocurarine to be present solely in hepatocytes; binding to ASOR did not affect the relative distribution in the various cell types. It is concluded that binding of cationic drugs to ASOR does not result in endocytosis of a drug-protein-receptor complex by the liver. This result rather suggests that dissociation of the organic cations from the asialoglycoprotein occurs within the liver before endocytosis of the glycoprotein.
D000818:Animals; D001212:Asialoglycoproteins; D001692:Biological Transport; D002412:Cations / Q000378:metabolism; D002451:Cell Compartmentation; D004705:Endocytosis; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D009961:Orosomucoid / Q000031:analogs & derivatives* / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism*; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D014326:Tropanes / Q000378:metabolism*; D014403:Tubocurarine / Q000378:metabolism*
D001212:Asialoglycoproteins; D002412:Cations; D009961:Orosomucoid; D000644:Quaternary Ammonium Compounds; D014326:Tropanes; C017030:asialoorosomucoid; C021174:deptropine methobromide; D014403:Tubocurarine