metyraPONE (Monograph)

Drug class: Pituitary Function
VA class: DX900
CAS number: 54-36-4

Medically reviewed by Drugs.com on Nov 21, 2024. Written by ASHP.

Introduction

Metyrapone, a synthetic pyrimidine base that blocks the activation of various steroid hormones, is used to evaluate hypothalamic-pituitary function.

Uses for metyraPONE

Metyrapone is used to evaluate hypothalamic-pituitary function. The drug is used to evaluate anterior pituitary reserve of ACTH in the diagnosis of hypopituitarism and to differentiate Cushing’s syndrome caused by adrenal adenoma from that caused by adrenal hyperplasia. Since subnormal response to metyrapone may be the result of either primary adrenal insufficiency or reduced pituitary function, primary adrenal insufficiency must be ruled out before performing the metyrapone test. This is especially important in patients with frank hypoadrenocorticism because administration of metyrapone may lead to acute adrenal insufficiency by inhibiting secretion from minimally functioning adrenals. (See Cautions: Precautions and Contraindications.)

Some clinicians believe that the metyrapone test provides a relatively insensitive measure of pituitary function. However, as a test of hypothalamic-pituitary-adrenal axis function, metyrapone is considered less dangerous and better tolerated than vasopressin or bacterial pyrogens. The metyrapone test for endogenous ACTH reserve has exhibited reliability similar to or greater than the insulin hypoglycemia test and is usually preferred to the latter test, especially in pediatric patients. Metyrapone may be used to confirm dexamethasone suppression test results in the differential diagnosis of adrenal hyperplasia and adrenal adenoma, but because some patients with adrenal adenoma respond to metyrapone, the results of this test must be interpreted cautiously.

Metyrapone has been used to control hypercortisolism secondary to ACTH- secreting tumors^{† [off-label]}, but compensatory increase in endogenous ACTH usually occurs after a few days, negating the effects of metyrapone therapy. The drug has also been used with spironolactone and prednisone to relieve severe edema, but its use in this situation has been replaced by more potent diuretics. Metyrapone has also been used to lower plasma cholesterol concentrations^{† [off-label]} in patients with familial hypercholesterolemia type II, but well-controlled clinical studies evaluating the drug’s effectiveness in this condition are not yet available.

metyraPONE Dosage and Administration

Administration

Metyrapone is administered orally. Metyrapone may be taken with milk or food to reduce GI irritation.

Dosage

Four days prior to the metyrapone test, a control 24-hour urine specimen is collected and assayed for 17-OHCS or 17-KGS. (Alternatively, some clinicians recommend determination of urinary THS.) On the following day, a corticotropin test is performed to rule out adrenocortical insufficiency. If adrenal insufficiency is not demonstrated, the metyrapone test may begin after 2 days without medications. Adults may be given a metyrapone dose of 750 mg (approximately 15 mg/kg) orally every 4 hours for 6 doses. Children may be given a metyrapone dose of 15 mg/kg or 300 mg/m² orally every 4 hours for 6 doses; a minimum single dose of 250 mg is recommended by the manufacturer. On the day following administration of metyrapone, another 24-hour urine specimen is collected and urinary 17-OHCS and 17-KGS are measured.

As an alternative to the multiple-dose oral metyrapone schedule, a test using a single 30 mg/kg oral dose of metyrapone, administered at midnight, has been used in adults^{† [off-label]}. Urine samples are obtained and analyzed for 17-OHCS and 17-KGS as in the multiple-dose schedule. Alternatively, plasma samples may be obtained prior to, and at 8 a.m. on the day following, administration of metyrapone and assayed for compound S. Some clinicians believe that the single dose metyrapone procedure is safer, simpler, and more reliable than the multiple-dose procedure.

Individuals with a normal pituitary-adrenal axis will respond to metyrapone with a 2- to 4-fold increase in 17-OHCS urinary excretion or doubling of 17-KGS excretion. A normal response to metyrapone produces urinary THS concentrations of greater than 500 mcg/day and plasma compound S concentrations 4–5 times greater than control concentrations. In patients without adrenal insufficiency, failure to respond to metyrapone is generally interpreted as evidence of pituitary-adrenal reserve impairment and, by inference, reflects a defect in the CNS-pituitary mechanisms governing ACTH release. Specifically, patients with hypopituitarism show no significant increase in the excretion of the urinary steroids. Panhypopituitarism can be distinguished from partial hypopituitarism, because a partial response to exogenous corticotropin is exhibited in the latter disorder while patients with panhypopituitarism fail to respond to corticotropin. Patients with Cushing’s syndrome secondary to adrenal hyperplasia respond with urinary steroid increments in excess of those seen in normal patients, whereas patients with Cushing’s syndrome secondary to adrenal adenoma usually exhibit no change in urinary steroids. A subnormal response to metyrapone may occur in pregnant women and in patients with hypothyroidism.

Cautions for metyraPONE

Adverse Effects

Metyrapone has a low order of toxicity. Nausea, abdominal discomfort, dizziness, vertigo, headache, sedation, and allergic rash have been reported. Occasionally, arterial blood pressure may fall and a moderate increase in pulse rate may ensue. Decreased leukocyte count and bone marrow depression have occurred rarely.

Precautions and Contraindications

All corticosteroid therapy should be discontinued prior to and during the metyrapone test. Metyrapone may potentially produce acute adrenal insufficiency and even death in patients with reduced adrenal secretory capacity and, therefore, the drug should not be used in patients with adrenocortical insufficiency.

Metyrapone is contraindicated in patients with known hypersensitivity to the drug.

Carcinogenicity

Long-term studies to determine the carcinogenic potential of metyrapone in animals have not been performed to date.

Pregnancy and Fertility

Pregnancy

Animal reproduction studies have not been performed with metyrapone. In women who received the metyrapone test during the second or third trimester of pregnancy, there was evidence of inhibition of 11-β-hydroxylation by the drug in fetal pituitary. The effect of the drug on reproduction is not known. Safe use of metyrapone in pregnant women has not been established, and the drug should be used during pregnancy only when clearly needed.

Lactation

Since it is not known whether metyrapone distributes into milk, the drug should be used with caution in nursing women.

Drug Interactions

Phenytoin enhances first-pass liver metabolism of metyrapone and, thus, may invalidate metyrapone test results. Phenytoin therapy should be discontinued at least 2 weeks prior to the metyrapone test. Some clinicians suggest that the effect of phenytoin on plasma metyrapone concentrations can be overcome by doubling the oral dose of metyrapone.

Subnormal response to metyrapone may also occur in patients receiving estrogens, progestins, corticosteroids, phenothiazines, chlordiazepoxide, chlorpromazine, amitriptyline, phenobarbital, or methysergide. Estrogen-progestin oral contraceptives have been reported to both reduce and elevate response to metyrapone.

Pharmacology

Metyrapone inhibits the normal 11-β-hydroxylation of 11-desoxycortisol (compound S), 11-desoxycorticosterone (DOC), and aldosterone precursors in the adrenal cortex, thus blocking conversion of compound S to hydrocortisone (cortisol), DOC to corticosterone, and aldosterone precursors to aldosterone. Unlike hydrocortisone, compound S has practically no inhibitory effect on corticotropin releasing factor (CRF). Decreased plasma hydrocortisone concentrations, therefore, stimulate negative feedback mechanisms for consecutive release of CRF and corticotropin (ACTH). In normal patients, the compensatory release of ACTH accelerates production of compound S, DOC, and aldosterone precursors. In patients with hypopituitarism, compensatory release of ACTH cannot occur and, therefore, plasma concentrations of compound S, DOC, and aldosterone precursors do not increase, nor does urinary excretion of their metabolites—tetrahydro-11-desoxycortisol (THS), 17-hydroxycorticosteroids (17-OHCS), and 17-ketogenic steroids (17-KGS)—increase.

In high doses, metyrapone may inhibit 18- and 19-hydroxylase enzymes, thus inhibiting synthesis of other steroids, including estrogens. Through extra-adrenal mechanisms, the drug may also decrease plasma half-life of hydrocortisone, increase growth hormone release, and induce hyperglycemia.

metyraPONE Pharmacokinetics

Absorption

GI absorption of metyrapone is variable. Following oral administration of 750 mg of metyrapone every 4 hours to normal patients, peak plasma concentrations of about 1.2 mcg/mL are reached after the third dose; plasma concentrations of 0.4 mcg/mL are present immediately after the sixth dose. Inhibition of 11-β-hydroxylase sharply decreases within 4 hours after an oral dose of metyrapone.

Elimination

Metyrapone has a plasma half-life of about 20–26 minutes.

Metyrapone is rapidly metabolized in the liver and kidneys to its reduced metabolite which is active; metabolism of metyrapone may be delayed in patients with liver disease. Within 2 days following oral administration of 750 mg of metyrapone every 4 hours for 6 doses, approximately 0.5% of the drug is excreted in urine unchanged, 3% is excreted as the reduced metabolite, and 37% as glucuronide conjugates of metyrapone and its metabolites.

Chemistry and Stability

Chemistry

Metyrapone is a synthetic pyrimidine base. The drug occurs as a white to light amber, fine, crystalline powder having a characteristic odor. The drug is sparingly soluble in water and freely soluble in alcohol.

Stability

Metyrapone darkens when exposed to light. Commercially available metyrapone tablets should be stored in tight, light-resistant containers. Metyrapone tablets should be protected from excessive heat and light to prevent discoloration and degradation.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.