Divigel Mechanism of Action

Pharmacology: Pharmacodynamics: The pharmacodynamics of Divigel are similar to those of oral estrogens, but the major difference to oral administration lies in the pharmacokinetic profile. The clinical efficacy of Divigel in the treatment of menopausal symptoms is comparable to that of peroral estrogen. Combined with medroxyprogesterone acetate, percutaneous estradiol treatment lowers total cholesterol without reducing the HDL-cholesterol level.
Pharmacokinetics: Divigel is an alcohol-based estradiol gel. When applied to the skin the alcohol evaporates rapidly and estradiol is absorbed through the skin into the circulation. To some extent, however, the estradiol is stored in subcutaneous tissue from where it is released gradually into circulation. Percutaneous administration circumvents the hepatic first-pass metabolism. For these reasons, the fluctuations in the plasma estrogen concentrations with Divigel are less pronounced than with peroral estrogen.
A 1.5 mg percutaneous dose of estradiol (1.5 g Divigel) results in a plasma concentration of about 340 pmol/l, which corresponds to the level of early follicular stage in premenopausal women. During Divigel treatment, the estradiol/estrone ratio remains at 0.7, while during peroral estrogen treatment it usually drops to less than 0.2. The mean estradiol at steady state of Divigel is 82 percent compared with an equivalent oral dose of estradiol valerate. Otherwise the metabolism and excretion of transdermal estradiol follow the fate of natural estrogens.
Toxicology: Preclinical safety data: Estradiol is a natural female hormone with an established clinical use, therefore no toxicological studies have been performed with Divigel. The necessary studies on the irritant effects of the gel have been studied in rabbits and skin sensitisation in guinea pig. Based on the results from these studies it can be concluded that Divigel very infrequently could cause mild skin irritation. The frequency of the occurrence of dermal irritation can be reduced by daily change of the application site.