Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Diagnostic agent, test for pituitary function, ATC code: V04CD01.

Metopirone acts by inhibiting adrenocorticosteroid synthesis. It reduces cortisol and corticosterone production by inhibiting the 11β-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotrophic hormone (ACTH) production by the pituitary. Continued blockade of the enzymatic steps leading to production of cortisol and corticosterone produces a marked increase in adrenocortical secretion of their immediate precursors, 11β- hydroxylation and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding increase in plasma levels of these steroids and of their metabolites in the urine. These metabolites can easily be determined by measuring urinary 17- hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Metopirone is used as a diagnostic test on the basis of these properties, with plasma 11- desoxycortisol and urinary 17- OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in mild natriuresis.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Metyrapone is rapidly absorbed and eliminated from the plasma after oral administration.
Absorption: Peak plasma concentrations are usually reached one hour after oral administration.

Distribution: After administrationof 750 mg mean peak plasma concentrations are 3.7 microg/ml falling to 0.5 microg/ml 4 hours after administration.

Biotransformation: Metyrapol, the reduced form of metyrapone, is the main active metabolite. Eight hours after a single oral dose, the ratio of metyrapone in the plasma is 1:1.5. Metyrapol takes about twice as long as metyrapone to be eliminated in the plasma.

Elimination: The plasma elimination half-life of Metopirone is about 2 hours after oral administration. Seventy-two hours after a first daily dose of 4.5g Metopirone (750mg every 4 hours), 5.3% of the total dose was excreted in the urine as metyrapone (9.2% in free form and 90.8% conjugated with glucuronic acid), and 38.5% in the form of metyrapol, the principal active metabolite (8.1% in free form and 91.9% conjugated with glucuronic acid).