Mepyrapone Other names: Metyrapone Metyrapon Methapyrapone Methopirapone Methbipyranone Methopyrinine Methopyrapone Metroprione Methopyrone

Metyrapone inhibits the enzyme responsible for the 11β-hydroxylation stage in the biosynthesis of cortisol and to a lesser extent, aldosterone. The fall in plasma concentration of circulating glucocorticoids stimulates ACTH secretion, via the feedback mechanism which accelerates steroid biosynthesis. As a result, 11-desoxycortisol, the precursor of cortisol, is released into the circulation, metabolised by the liver and excreted in the urine. Unlike cortisol, 11-desoxycortisol does not suppress ACTH secretion and its urinary metabolites may be measured.

These metabolites can easily be determined by measuring urinary 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Metyrapone 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. Metyrapone may also suppress biosynthesis of aldosterone, resulting in mild natriuresis.

Metyrapone is rapidly absorbed and eliminated from the plasma. Peak plasma levels usually occur one hour after ingestion of metyrapone; after a dose of 750mg metyrapone, plasma drug levels average 3.7μg/ml. Plasma drug levels decrease to a mean value of 0.5μg/ml 4 hours after dosing. The half-life of elimination of metyrapone from the plasma is 20 to 26 minutes.

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

Seventy-two hours after a first daily dose of 4.5g metyrapone (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 (8.1% in free form and 91.9% conjugated with glucuronic acid).

Pre-clinical data for metyrapone reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity. Metyrapone was not mutagenic with or without metabolic activation in three strains of bacteria. Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with metyrapone. Currently, there are no available non-clinical studies conducted to investigate the genotoxicity, or carcinogenic potential of metyrapone.

Effects in pre-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.