12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these gonadotropins seen in postmenopausal women.
12.3 Pharmacokinetics
Absorption
Conjugated estrogens are water-soluble and are absorbed from the gastrointestinal tract after release from the drug formulation. The PREMARIN tablet releases conjugated estrogens slowly over several hours. Table 2 summarizes the mean pharmacokinetic parameters for unconjugated and conjugated estrogens following administration of 1 × 0.625 mg and 1 × 1.25 mg tablets to healthy postmenopausal women.
Food effect: The pharmacokinetics of PREMARIN 0.45 mg and 1.25 mg tablets were assessed following a single dose with a high-fat breakfast and with fasting administration. The Cmax and AUC of estrogens were altered approximately 3–13%. The changes to Cmax and AUC are not considered clinically meaningful, therefore PREMARIN may be taken without regard to meals.
| Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 0.625 mg | ||||
| PK Parameter Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t1/2 (h) | AUC (pg∙h/mL) |
| Estrone | 87 (33) | 9.6 (33) | 50.7 (35) | 5557 (59) |
| Baseline-adjusted estrone | 64 (42) | 9.6 (33) | 20.2 (40) | 1723 (52) |
| Equilin | 31 (38) | 7.9 (32) | 12.9 (112) | 602 (54) |
| Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 × 0.625 mg | ||||
| PK Parameter Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t1/2 (h) | AUC (ng∙h/mL) |
| Total Estrone | 2.7 (43) | 6.9 (25) | 26.7 (33) | 75 (52) |
| Baseline-adjusted total estrone | 2.5 (45) | 6.9 (25) | 14.8 (35) | 46 (48) |
| Total Equilin | 1.8 (56) | 5.6 (45) | 11.4 (31) | 27 (56) |
| Pharmacokinetic Profile of Unconjugated Estrogens Following a Dose of 1 × 1.25 mg | ||||
| PK Parameter Arithmetic Mean (%CV) | Cmax (pg/mL) | tmax (h) | t1/2 (h) | AUC (pg∙h/mL) |
| Estrone | 124 (30) | 10.0 (32) | 38.1 (37) | 6332 (44) |
| Baseline-adjusted estrone | 102 (35) | 10.0 (32) | 19.7 (48) | 3159 (53) |
| Equilin | 59 (43) | 8.8 (36) | 10.9 (47) | 1182 (42) |
| Pharmacokinetic Profile of Conjugated Estrogens Following a Dose of 1 × 1.25 mg | ||||
| PK Parameter Arithmetic Mean (%CV) | Cmax (ng/mL) | tmax (h) | t1/2 (h) | AUC (ng∙h/mL) |
| Total Estrone | 4.5 (39) | 8.2 (58) | 26.5 (40) | 109 (46) |
| Baseline-adjusted total estrone | 4.3 (41) | 8.2 (58) | 17.5 (41) | 87 (44) |
| Total equilin | 2.9 (42) | 6.8 (49) | 12.5 (34) | 48 (51) |
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 concentration in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin.
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 a 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 intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.