Glossary · Pharmacology

First-pass metabolism

Definition: First-pass metabolism is the metabolism of an orally absorbed drug by the gut and liver before it reaches systemic circulation. For oral estradiol, first-pass conversion to estrone in the liver and gut reduces circulating estradiol and stimulates hepatic synthesis of clotting factors and SHBG — which is why transdermal estrogen has a more favorable VTE profile than oral.

Detailed definition

After oral absorption, drugs pass through the portal circulation to the liver before entering systemic circulation. The gut wall and liver express phase I (cytochrome P450) and phase II (conjugation) enzymes that metabolize many drugs. For some drugs (estradiol, propranolol, lidocaine), first-pass metabolism is extensive enough that a substantial fraction of an oral dose is metabolized before reaching systemic circulation. Oral estradiol is rapidly converted to estrone and estrone-sulfate during first pass, with the active estradiol fraction reaching circulation at a fraction of the dose taken. The hepatic exposure also induces synthesis of sex hormone-binding globulin (SHBG), thyroid-binding globulin, certain coagulation factors (factor VII, factor VIII, fibrinogen), and triglycerides. These hepatic effects are the basis for the modestly higher VTE risk seen with oral vs. transdermal estrogen. Transdermal estrogen avoids first-pass metabolism by entering systemic circulation directly through the skin.

Why it matters in menopause

First-pass metabolism is the underlying reason transdermal estrogen has a more favorable VTE profile than oral estrogen. For women with a personal or family history of VTE, obesity, or other thrombotic risk factors, transdermal is strongly preferred. For oral progesterone, first-pass metabolism actually creates the allopregnanolone metabolite that produces the sleep-promoting effect — so the same mechanism that is a downside for estrogen is a benefit for progesterone.

Sources

External references: Wikipedia.

← Back to full glossary