Studies on phenolic steroids in human subjects

Abstract

6,7-³H-Estriol-16α-glucosiduronate-¹⁴C was administered to eight women (nine studies) by several routes: both injection and infusion (300 min) into the cubital vein, injection into the portal vein system, ingestion and instillation into the duodenum, jejunum, and ileum. Urine, collected from 0-2, 2-4, 4-8, 8-12, and 12-24 hr, was analyzed by countercurrent distribution for its content of radioactive 3- and 16-glucosiduronate (E₃-3Gl,E₃-16Gl) and sulfoglucosiduronate (E₃-3S,16Gl) of estriol as well as for ³H/¹⁴C ratio of each conjugate. After peripheral injection 50-60% of the injected E₃-16Gl was excreted unchanged along with about 5% as E₃-3S,16Gl with an unchanged ³H/¹⁴C ratio, indicating direct sulfation of the injected E₃-16Gl. During a 300 min infusion, urinary excretion closely resembled that following injection. But 2-4 hr after the end of the infusion excretion of E₃-3S, 16Gl stopped, excretion of E₃-3Gl (17%/24 hr) with an elevated ³H/¹⁴C ratio started, and excretion of E₃-16Gl continued (70%/24 hr), but with a rapidly increasing ³H/¹⁴C ratio. This indicated sequestration in a sluggishly metabolizing compartment where two processes occurred: (a) extensive hydrolysis of E₃-16Gl followed by reconjugation at either C3 or C16 with unlabeled uridine diphosphate glucuronic acid (UDPGA), thereby increasing the ³H/¹⁴C ratio; and (b) transconjugation from C16 to C3, thereby producing E₃-3Gl with finite ³H/¹⁴C ratios. Instillation into various segments of the small intestine produced results qualitatively similar to those after intravenous infusion, whereas ingestion and intraportal injection resembled peripheral intravenous injection. Therefore, we have postulated the possibility of an enteric circulation (in addition to an enterohepatic circulation) in which the steroid or its conjugates are transported into the small intestine in the succus entericus, modified, and then reabsorbed and excreted in the urine-a process which requires several hours.