First-pass effect of norethindrone in rabbits and rats

The influence of the route of administration on the pharmacokinetics of the synthetic progestogen norethindrone was studied in the rabbit and rat. In the rabbit, the area under the curve (AUC) after oral administration was 54% of that after i.v. administration. In the rat, the AUC after administration into the hepatic portal vein was 32% of AUCi.v.; after oral administration the AUCoral was 13.7% of AUCi.v. and 57.6% of AUCportal. Therefore, in both the rabbit and rat norethindrone is subject to a first-pass effect. Using the technique of constant withdrawal of blood from the hepatic portal vein after drug administration into the gastrointestinal tract, it was shown the norethindrone is metabolized in the gut wall. Hence, in the rat at least, there are both intestinal and hepatic components of the overall first-pass effect. In addition, increasing the time of intraportal injection from 15 sec to 2 min (thereby reducing the rate of drug delivery to the liver) resulted in the AUC being reduced by 40%. Dose-dependent kinetics were observed with doses of norethindrone greater than 500 microgram/kg.