Metyrapone

Drug Induced Liver Injury Rank (DILIrank 2.0)

Metyrapone

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

DRUG HAS SHOWN DIRECT INHIBITORY ACTION ON CARDIAC MUSCLE OF DOGS...& ISOLATED CARDIAC MUSCLE OF CATS. MICE DISPLAY CIRCADIAN RESPONSE TO IT WITH TOXICITY GREATEST @ 2100 HR. IN COWS, 8 G IV PRODUCED INCR IN SODIUM & DECR IN MAGNESIUM EXCRETION...16 OR 24 G...HAD OPPOSITE EFFECTS.

METYRAPONE.../IS/ NOW COMMONLY USED EXPTL AS INHIBITOR OF CYTOCHROME P450-DEPENDENT MONO-OXYGENATION, COMPETITIVELY INHIBITS N-HYDROXYLATION OF 4-CHLOROANILINE & 2-NAPHTHYLAMINE...

ITS MECHANISM OF INHIBITION IS NOT KNOWN WITH CERTAINTY. COMPD IS BOUND TO OXIDIZED CYTOCHROME & GIVES A TYPE II SPECTRUM...REPORTED TO COMPETITIVELY INHIBIT O-DEMETHYLATION OF P-NITROANISOLE...PARTIAL NONCOMPETITIVE INHIBITION OF N- & O-DEALKYLATION...ALSO...REPORTED...

INCR IN CONCN OF NADPH CAN CHANGE A REACTION FROM ONE WHICH IS INSENSITIVE TO METYRAPONE TO ONE WHICH IS INHIBITED... IT HAS BEEN POSTULATED...THAT.../IT/ INHIBITS BY COMPETING WITH OXYGEN FOR OXYGEN BINDING SITE OF CYTOCHROME P450.

Pregnant Sprague-Dawley rats at 72, 48, and 24 hrs prior to premature delivery at 21 days, or term delivery at 22 days of gestation, were injected intraperitoneally twice daily with 45 mg/kg of metyrapone (MTP), an adrenal 11-beta steroid hydroxylase inhibitor. Control animals received equivalent volumes of saline. MTP-treated offspring of 21 days gestational age had lower body weight and lung weight than controls, while body/lung weights were not different between offspring groups at day 22. At both gestational days studied, offspring of MTP-treated rats had significantly reduced lung disaturated phosphatidylcholine (DSPC) content compared to controls. Total phospholipids (TPL) content was not significantly different between groups at either gestational age. DSPC/TPL ratios were decreased in MTP-exposed offspring compared to controls (P<0.05) at days 21 and 22 of gestation. Activities of the antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase, were similarly reduced (P<0.01) in the lung of MTP offspring at both gestational days studied. Day 21 MTP-treated pups manifested a significantly decrease in survival rate compared with controls from 25 minutes after delivery (44% survival versus 83%, P<0.05) to 90 minutes after delivery (6% survival versus 78%, P<0.01).

ZS9KD92H6V

METYRAPONE

Established Pharmacologic Class [EPC] - Adrenal Steroid Synthesis Inhibitor

Mechanisms of Action [MoA] - Adrenal Steroid Synthesis Inhibitors

Metyrapone is an Adrenal Steroid Synthesis Inhibitor. The mechanism of action of metyrapone is as an Adrenal Steroid Synthesis Inhibitor.

METYRAPONE

Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033)

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Absorbed rapidly and well when administered orally. Peak plasma concentrations are usually reached 1 hour after administration.

After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% as glucuronide) and 38.5% in the form of metyrapol (8.1% free and 91.9% as glucuronide) within 72 hours after the first dose was given.

GASTROINTESTINAL ABSORPTION OF METYRAPONE IS VARIABLE. FOLLOWING ORAL ADMIN OF 750 MG OF METYRAPONE EVERY 4 HR TO NORMAL PT, PEAK PLASMA LEVELS OF ABOUT 1.2 UG M/L...REACHED AFTER THIRD DOSE...0.4 UG/ML...PRESENT IMMEDIATELY AFTER SIXTH DOSE.

...PLASMA LEVELS OF METYRAPONE...IN RATS WERE SHOWN TO EXHIBIT A CIRCADIAN PATTERN WHEN ANIMALS WERE KEPT IN ALTERNATING 12-HR LIGHT-12 HR DARK REGIMEN. HALF-LIFE...OBSERVED @ 10:00 PM WAS APPROX 2.5 TIMES LONGER THAN THAT OBSERVED @ 10:00 AM...

...WITHIN 2 DAYS FOLLOWING ORAL ADMIN OF 750 MG...EVERY 4 HR FOR 6 DOSES, APPROX 0.5%...IS EXCRETED IN URINE UNCHANGED, 3% IS EXCRETED AS REDUCED METABOLITE, & 37% AS GLUCURONIDE CONJUGATES OF METYRAPONE & ITS METABOLITES.