RT Journal Article SR Electronic T1 Futile Cycling of Estrone Sulfate and Estrone in the Recirculating Perfused Rat Liver Preparation JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 423 OP 436 VO 297 IS 1 A1 Eugene Tan A1 Thanh Lu A1 K. Sandy Pang YR 2001 UL http://jpet.aspetjournals.org/content/297/1/423.abstract AB The futile cycling of estrone sulfate (E1S) and estrone (E1) was investigated in the recirculating, perfused, rat liver preparation. Although E1S was not distributed into bovine erythrocytes, the compound was highly bound to albumin [4% bovine serum albumin (BSA), unbound fraction of 0.03 ± 0.01]. By contrast, E1 was bound and metabolized to estradiol (E2) by bovine erythrocytes, with metabolic clearances of 0.061 to 0.069 ml/min when normalized to the hematocrit. Due to strong binding of E1 to albumin, BSA (4%) greatly reduced the red cell clearance to a minimum (0.0024 to 0.0031 ml/min/unit of hematocrit). Despite the low unbound fractions of E1S (0.027 ± 0.004) and E1 (0.036 ± 0.006), clearances of the simultaneously delivered tracers [3H]E1S and [14C]E1in perfusate (4% BSA and 20% erythrocytes) by the recirculating, perfused rat liver (flow rate of 0.91 ± 0.1 ml/min/g of liver) were high (0.53 ± 0.08 and 0.85 ± 0.2 ml/min/g of liver, respectively). Although low levels of [3H]E1were observed following the tracer [3H]E1S, both parent and metabolite species displayed similar decay half-lives that were characteristic of compounds undergoing futile cycling. The same decay profile was observed for [14C]E1S but the half-life of administered [14C]E1 was shorter in comparison. A series-compartment liver model that incorporated previously noted heterogeneity in estrone sulfation and glucuronidation activities among periportal and perivenous hepatocytes, and homogeneity in sinusoidal transport and desulfation was used to explain the discrepant half-lives. The model described a high partitioning of E1 in the endoplasmic reticulum and the segregation of estrone sulfation activities in the cytosolic space from the desulfation and glucuronidation activities in the endoplasmic reticulum space. The American Society for Pharmacology and Experimental Therapeutics