PHARMACOKINETIC AND PHARMACOLOGICAL VARIATION BETWEEN DIFFERENT ESTROGEN PRODUCTS

Due to the complex nature of endogenous and exogenous hormone concentr ations, formation, and metabolism and assay complexity, the pharmacoki netics of estrogens are difficult to study. Oral estrogens have minima l systemic bioavailability (2% to 10%) due to gut and liver (first-pas s) metabolism. High concentrations of estrone are achieved with oral a dministration, whereas higher concentrations of estradiol are generall y achieved after percutaneous absorption. Although vaginal products (s uch as gel, rings, etc.) are administered locally, they achieve high s erum concentrations. Estradiol and estrone concentrations and estradio l-to-estrone ratios vary with different estrogen therapies. Approximat ely 95% to 98% of estradiol is bound loosely to albumin or tightly to sex hormone binding globulin, the major binding protein. The terminal half lives for the different estrogen compounds (after oral or intrave nous administration) vary from 1-12 hours. Some conversion rates have been calculated between estrogen and its metabolites. Smoking decrease s achievable estrogen concentrations, and has a greater effect on oral products. Oral contraceptives have been found to decrease antipyrine clearance. In the one study evaluating conjugated estrogens, antipyrin e clearance was not altered. Oral contraceptives have a variable effec t on the elimination of medications. Acetaminophen clearance is increa sed, whereas clearance of some benzodiazepines, caffeine, and predniso lone is decreased. Phenytoin increases the metabolism of conjugated es trogens. The various estrogen products may produce different clinical effects based on composition. The metabolites (minor components) of co njugated estrogens have been found to have significant effects on lipi d concentrations, uterine weight, liver generated compounds, and bone resorption. Because transdermal products bypass the first-pass effect, delayed or decreased effects on lipid profiles and liver generated co mpounds have been observed.