Bioavailability of Norethindrone in Rabbits after Administration of Norethindrone Acetate in Single, Double and Quadruple Doses Released Through Subcutaneous Silastic Implants

Plasma level of norethindrone (NET) and in vivo release of norethindrone acetate (NETA) were studied in three groups of albino rabbits (5 animals/group) after insertion of one, two and four subcutaneous implants, each containing 40 mg crystalline NETA over a period of 24 weeks. The ratios of the in vivo release rate of steroid were 1, 1.9 and 3.9 in the animals of group 1 (one implant), group II (two implants) and group III (four implants) respectively. Thus, the in vivo release rate in group II and III showed an increase which was almost twice and four times as great as that of group I. However, the mean ratios of the serum NET levels were 1, 1.2 and 2.4 in animals of group I, II and III respectively. Thus, interestingly, the serum NET level did not show the expected twofold and fourfold increase and lacked correlation with the in vivo release. Although the insertion of multiple implants gives multiple increases in the in vivo steroid release, it does not give rise to a multiple increase in the serum levels of the steroid. It is possible that there is a kind of a threshold of steroid concentration in the animals when they are loaded with exogenously administered steroid. When the steroid concentration tends to cross the threshold level, pharmacokinetic or pharmacodynamic processes of the animal work maximum to hold down the steroid level in blood plasma.