Premarin pharmacokinetics and molecular data
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
List of indications
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, PREMPRO and PREMPHASE
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 PREMPRO 0.625 mg/2.5 mg
and 2 PREMPRO 0.625 mg/5 mg tablets to healthy postmenopausal women.
Food-Effect
Single dose studies in healthy, postmenopausal women were conducted to
investigate any potential drug interaction when PREMPRO or PREMPHASE 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%.
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.
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.
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.
Adapted from the FDA Package Insert.