The affinity of norgestimate for uterine progestogen receptors and its direct action on the uterus

Abstract

Norgestimate is a new orally active progestational agent. Studies were conducted to demonstrate that norgestimate is active pharmacologically without requiring biotransformation to an active metabolite. In in vitro studies, norgestimate exhibited a relatively high affinity for the rabbit uterine progestogen receptor. To demonstrate that norgestimate was not being degraded to a biologically active entity, which was binding to receptor sites in the cytosol preparation, the stability of 14C-norgestimate in the preparation was determined. Following the incubation of 14C-norgestimate with the cytosol fraction used in the receptor assay, the labeled material was extracted and analyzed by reverse phase high performance liquid chromatography. 14C-Norgestimate was recovered from these incubation mixtures, confirming that norgestimate was available to bind to the progestogen receptor. In in vivo studies, norgestimate stimulated the endometrium in immature rabbits when applied directly to the uterus, again suggesting that biotransformation to an active metabolite is not required for expression of norgestimate's pharmacological activity. These in vitro and in vivo studies, when considered with previously reported studies, show that norgestimate is a unique progestogen.