Due to the complex nature of endogenous and exogenous hormone concentration, formation, and metabolism and assay complexity, the pharmacokinetics of estrogen are difficult to study. Oral estrogens have minimal systemic bioavailability (2% to 10%) due to gut and liver (first-pass) metabolism. High concentrations of estrone are achieved with oral administration, whereas higher concentrations of estradiol are generally achieved after percutaneous absorption. Although vaginal products (such as gel, rings, etc.) are administered locally, they achieve high serum concentrations. Estradiol and estrone concentrations and estradiol-to-estrone ratios vary with different estrogen therapies. Approximately 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 intravenous administration) vary from 1-12 hours. Some conversion rates have been calculated between estrogen and its metabolites. Smoking decreases 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, antipyrine clearance was not altered. Oral contraceptives have a variable effect on the elimination of medications. Acetaminophen clearance is increased, whereas clearance of some benzodiazepines, caffeine,and prednisolone is decreased. Phenytoin increases the metabolism of conjugated estrogens. The various estrogen products may produce different clinical effects based on composition. The metabolites (minor components) of conjugated estrogens have been found to have significant effects on lipid 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 compounds have been observed.