Premarin pharmacokinetics and molecular data

Pharmacokinetics
Absorption Food-Effect Distribution Metabolism Excretion

Absorption
Conjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. However, Premarin contain a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. MPA is well absorbed from the gastrointestinal tract. Table 1 summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens, and medroxyprogesterone acetate following administration of 2 Premarin 0.625 mg/2.5 mg and 2 Premarin 0.625 mg/5 mg tablets to healthy postmenopausal women. Return to top

Food-Effect
Single dose studies in healthy, postmenopausal women were conducted to investigate any potential drug interaction when Premarin is administered with a high fat breakfast. Administration with food decreased the Cmax of total estrone by 18 to 34% and increased total equilin Cmax by 38% compared to the fasting state, with no other effect on the rate or extent of absorption of other conjugated or unconjugated estrogens. Administration with food approximately doubles MPA Cmax and increases MPA AUC by approximately 20 to 30%. Return to top

Distribution
The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. MPA is approximately 90% bound to plasma proteins but does not bind to SHBG. Return to top

Metabolism
Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occurs primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. Return to top

Excretion
Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Most metabolites of MPA are excreted as glucuronide conjugates with only minor amounts excreted as sulfates. Return to top