Long-acting contraceptive agents: the influence of physico-chemical properties of some esters of norethisterone upon the plasma levels of free norethisterone.
Four 17 beta-esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one), formulated both as oily solutions and aqueous suspensions, were administered intramuscularly to rabbits and free plasma levels measured for periods up to 9 weeks. For all formulations of the compounds, the disappearance of norethisterone following peak plasma levels obeyed first-order kinetics. Since different slope values were obtained for different formulations of the same compound, the values reflected the release rates of the esters from the formulations. Fusion data, partition coefficients and solubilities of the compounds in 2,2,4-trimethylpentane and water were obtained and these properties were related to the biological activity of the formulations. For oily solutions, the differences in plasma levels were ascribed to the different partition coefficients of the esters between the oil and tissue fluids. For suspensions, the different activity in relation to an oily solution of an ester was related to the strength of intermolecular forces in the crystal lattice and to the relative thermodynamic activity in the two formulations. The results demonstrate that microcrystalline suspensions do not always have a longer duration of activity than oily solutions of the same compound after intramuscular injection.
D000818:Animals; D003692:Delayed-Action Preparations; D004952:Esters; D005260:Female; D007700:Kinetics; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology; D011817:Rabbits; D012996:Solutions; D013329:Structure-Activity Relationship; D013535:Suspensions
D003692:Delayed-Action Preparations; D004952:Esters; D012996:Solutions; D013535:Suspensions; D009640:Norethindrone