THE EXCRETION OF TRITIUM-LABELED CHLORMADINONE ACETATE, MESTRANOL, NORETHINDRONE, AND NORETHYNODREL IN RATS AND THE ENTEROHEPATIC CIRCULATION OF METABOLITES

¹ The Toxicology Center, Department of Pharmacology, College of Medicine, University of Iowa

The excretion of tritium-labeled chlormadinone acetate (CA), mestranol (M), norethynodrel (NL), and norethindrone (N) was studied in female rats. Each steroid was rapidly and extensively eliminated as metabolites in the bile after single intravenous doses (0.161 µmol/kg) in animals prepared with bile fistulae. The cumulative percentages of administered radioactivity appearing in the bile at the end of an 8-hr period were: CA, 65%; M. 69%; NL, 71%; and N, 80%. With the exception of CA, each steroid appeared in the bile primarily as glucuronide conjugates and other polar materials which were not sulfate conjugates. Intact female rats given single intraperitoneal doses of the labeled steroid eliminated radioactive metabolites in the urine and feces at a much slower rate than that seen in the bile of animals prepared with biliary fistulae. Focal excretion was the major route of elimination in intact animals for all steroids and accounted for 80% or more of the radioactive dose by the end of 7 days. Experiments were conducted to assess the enterohepatic circulation (EHC) of metabolites of the steroids. Over one-half of the intraduodenally infused radioactivity associated with the biliary metabolites of M (59%) and N (64%), and 34% of the infused radioactivity associated with the biliary metabolites of CA underwent EHC and appeared in the bile during a 24-hr period. The glucuronide conjugate fraction of biliary metabolites was found to be quantitatively the most important fraction undergoing EHC. The polar metabolites, which could not be hydrolyzed by -glucuronidase, were not absorbed from the intestine and re-excreted in the bile. EHC was shown to be an important feature of the disposition of the contraceptive steroids in rats and was dependent on the excretion of glucuronide conjugates of steroid metabolites in the bile.

Note:
Acknowledgment. C. Daniel Meyer contributed excellent technical assistance in this research.