| Description |
Physiological pharmacokinetic models are derived from basic considerations of physiological, anatomical, and pharmacologic principles. These modes can simultaneously predict drug levels in blood, organs, and tissues. The prediction by the model depends on the following factors: dosage, partition coefficient, metabolism rate, excretion rate, protein binding, the rout of administration, and the rate of blood flow through organs and tissues. These factors were determined for norethindrone in rats and entered into the kinetic model separately so that their effects on the kinetics of norethindrone distribution could be studied. In rats, norethindrone was found to be eliminated mainly by liver metabolism with a metabolic clearance rate (MCR) of 501 ± 46 ml/hr. Renal excretion and biliary excretion of norethindrone was extremely small, although metabolites of norethindrone were excreted mainly by these means. Norethindrone is highly bound to tissue components. Every tissue studies showed that at concentrations in the range of 10[-8]M - 10[-6]M greater than 76% of the norethindrone was bound to macromolecular fractions. In the following tissues: liver, GI, uterus, and fat, bound norethindrone greater than 92% and the liver nearly 99%. Progestins are now being administered by the uterine intraluminal route for the purpose of effecting contraception. Therefore, the pharmacokinetics model was applied to predict norethindrone distribution in the body after the following routes of administration: i.v. injection, i.v. infusion, peroral intubation, uterine intraluminal perfusion, and uterine intraluminal instillation in order to assess the relative availability of the steroid in uterus and other parts of the body. Absorption of norethindrone from the luminal cavity of the uterus was very fast. Instantaneous absorption was observed when a small volume of norethindrone solution was instilled in the luminal cavity. Absorption of norethindrone from the GI tract, however, is slow, particularly in the presence of food. The bioavailability of norethindrone after peroral administration was relatively low (AUC[po] 11.5% if AUC[iv]). The concentration of norethindrone in the uterus was much higher after uterine intraluminal administration than other routes of administration studies. However, the levels of norethindrone in other tissue were much lower after uterine intraluminal administration than other routes of administration. The norethindrone concentrations determined experimentally and that predicted by the kinetic model were compared for each tissue in each route of administration. Generally the model adequately predicted norethindrone levels in each case. These experiments showed that the kinetic model and the parameters selected are suitable for the prediction of norethindrone levels in organs and tissues after various routes of administration. |
