TRANSPORT, BINDING, AND METABOLISM OF SULFATE CONJUGATES IN THE LIVER

Sulfate conjugates are a heterogeneous class of polar, anionic metabol ites that result from the conjugation of endogenous and exogenous comp ounds. 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 acti vity is slightly higher in the periportal than in the perivenous (cent rilobular) region of the liver, but recent immunohistochemical studies imply that specific isoforms of the sulfotransferases may also be pre ferentially localized in the perivenous region. Entry of sulfate conju gates 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 presen tly unknown. The removal of sulfates is usually by way of biliary excr etion while, on occasion, sulfates can be desulfated and participate i n futile cycling with their parent compounds. The binding, transport, and hepatic, elimination of various drug sulfate conjugates are examin ed. Non-recirculating studies carried out in the perfused rat liver wi th the multiple indicator dilution technique under varying input sulfa te conjugate concentrations have; provided essential information on th e effects of vascular (red blood cells and plasma protein) binding on transport and removal of the conjugates. These studies clearly demonst rate the need to study protein binding, transmembrane transfer charact eristics across the liver basolateral (sinusoidal) and canalicular mem branes, and enzyme zonation in a distributed-in-space fashion in order to properly define the handling of sulfate conjugates in the liver.