Transport, binding, and metabolism of sulfate conjugates in the liver.
Sulfate conjugates are a heterogeneous class of polar, anionic metabolites that result from the conjugation of endogenous and exogenous compounds. Sulfate conjugates exhibit a high degree of binding to albumin, the extent of which usually exceeds those of their parent compounds. Preponderant direct and indirect evidence suggests that sulfation activity is slightly higher in the periportal than in the perivenous (centrilobular) region of the liver, but recent immunohistochemical studies imply that specific isoforms of the sulfotransferases may also be preferentially localized in the perivenous region. Entry of sulfate conjugates into the liver cell is poor unless discrete carriers are present. Although known transport carriers exist for the sulfated bile acids, the specificity of the carriers for drug sulfate conjugates is presently unknown. The removal of sulfates is usually by way of biliary excretion while, on occasion, sulfates can be desulfated and participate in futile cycling with their parent compounds. The binding, transport, and hepatic elimination of various drug sulfate conjugates are examined. Non-recirculating studies carried out in the perfused rat liver with the multiple indicator dilution technique under varying input sulfate conjugate concentrations have provided essential information on the effects of vascular (red blood cells and plasma protein) binding on transport and removal of the conjugates. These studies clearly demonstrate the need to study protein binding, transmembrane transfer characteristics across the liver basolateral (sinusoidal) and canalicular membranes, and enzyme zonation in a distributed-in-space fashion in order to properly define the handling of sulfate conjugates in the liver.
Pang
K S
KS
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Schwab
A J
AJ
Goresky
C A
CA
Chiba
M
M
D000818:Animals; D015239:Arylsulfotransferase / Q000187:drug effects / Q000378:metabolism; D001646:Bile / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism*; D014018:Tissue Distribution
D012709:Serum Albumin; D013431:Sulfates; D015239:Arylsulfotransferase