STUDIES ON THE ANTIFERTILITY EFFECT AND METABOLISM OF A NEW, POSTCOITAL ORAL CONTRACEPTIVE, 2-METHYL-3-ETHYL-4-PHENYL-⁴-CYCLO-HEXENE CARBOXYLIC ACID, SODIUM SALT (ORF-4563)

¹ Department of Pharmacology, Ortho Research Foundation, Raritan, New Jersey

The administration of 25 µ/kg of 2-methyl- 3-ethy1- 4-pheny1-⁴-cyclohexene carboxylic acid, sodium salt (ORF-4563), once p.o. to female rats on the morning of sperm deposition prevents pregnancy. This antifertility effect of ORF-4563 is blocked by the administration of -diethylaminoethyldiphenylpropylacetate (SKF-525A), but SKF-525A does not block the antifertility activity of certain p-substituted derivatives of ORF-4563. In the rabbit much higher doses of ORF-4563 than in the rat are needed to prevent pregnancy when the compound is given p.o. 24 hr after mating. The compound is excreted via the kidney much more rapidly in the rabbit than the rat with less than 1% appearing in the urine as unchanged material. Conversion of the ED5O in rabbits to the ED100 was accomplished by the conjunct administration of probenecid. Interestingly, concentrations of the drug or metabolite much higher than those found in the oviducal fluid during tubal passage of fertilized rabbit ova are required to interfere with pregnancy when the drug is given by intraoviducal injection or by prior exposure of the eggs in vitro. Factors such as concentration of drug, duration of contact, structural specificity, etc., are only a beginning to an understanding of the mechanism of action. In labeled drug-distribution studies in the rabbit, highest amounts at 4 hr were found in bladder urine, then in serum, kidney and bile. Examination of oviducal fluid, which was continuously collected and removed daily, showed peak levels of the drug at 48 hr and a persistence for several days. One metabolite in rabbit urine was nearly twice as active an estrogen as the parent compound.