Pharmacokinetics and biotransformation of norethisterone in animals. A review

Abstract Norethisterone (NET) which is the active principal of several progestins is absorbed rapidly and completely in a wide range of doses in laboratory animals. Oral bioavailability (BV) is incomplete and variable due to the species-specific degree of first-pass metabolisation. Highest BV is reported for rabbits, lowest for rats and rhesus monkey. In rats and rabbits BV is reduced after experimental liver enzyme induction. At least in the rat, NET is metabolically changed both by the gut wall and the liver. Aromatisation to ethinyl estradiol is not observed. NET plasma levels decrease rapidly. Depending on the species, the terminal half-life is between 0.7 and 7 hours indicating no accumulation during daily treatment schedule. NET widely distributes to organs and tissues but does not show a specific enrichment in any organ. Only a minor part of an oral dose reaches the fetuses of rats and rhesus monkeys. The renally eliminated part of the dose varies with the animal species investigated. In the rat most of the dose is eliminated via the liver. Biliary metabolites are subject to enterohepatic circulation, whose degree is shown to be dependent upon gut bacteria. In vitro studies show that in principle the ethinyl group can be split off and the 4,5-epoxide may be formed. It is, however, questionable whether those metabolic conversions have any significance for in vivo biotransformation.