Fomepizole
Encyclopedia
Fomepizole or 4-methylpyrazole is indicated for use as an antidote
in confirmed or suspected methanol
or ethylene glycol
poisoning. It may be used alone or in combination with hemodialysis
. Apart from medical uses, the role of 4-methylpyrazole in coordination chemistry has been studied.
, the enzyme that catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.
When used as an antidote in cases of methanol or ethylene glycol poisoning, fomepizole is administered by injection. Fomepizole is supplied as brand name Antizol in 1.5 mL vials containing 1500 mg of fomepizole. The cost per vial is around $1000 when purchased as a brand name product as of 2010, and therefore is not widely stocked in some hospital pharmacy stocks.
Raptor Pharmaceuticals is investigating 4-methylpyrazole as possible solution to curing "Asian Glow" or "Asian Flush" due to ALDH2
deficiency. The drug is currently named Convivia and has completed Phase 2a of FDA clinical trails showing that it did have success in reducing acetaldehyde
levels in subjects with ALDH2 deficiency.
Following multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system.
In healthy volunteers, 1 to 3.5% of an administered dose was excreted unchanged in the urine. The metabolites also are excreted unchanged in the urine.
Fomepizole is dialyzable
.
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
in confirmed or suspected methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
or ethylene glycol
Ethylene glycol
Ethylene glycol is an organic compound widely used as an automotive antifreeze and a precursor to polymers. In its pure form, it is an odorless, colorless, syrupy, sweet-tasting liquid...
poisoning. It may be used alone or in combination with hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
. Apart from medical uses, the role of 4-methylpyrazole in coordination chemistry has been studied.
Medical use
Fomepizole is a competitive inhibitor of alcohol dehydrogenaseAlcohol dehydrogenase
Alcohol dehydrogenases are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide...
, the enzyme that catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites.
- Ethylene glycol is first metabolized to glycolaldehydeGlycolaldehydeGlycolaldehyde is the smallest possible molecule that contains both an aldehyde group and a hydroxyl group. It is the only possible diose, a 2-carbon monosaccharide, although a diose is not strictly a saccharide...
which then undergoes further oxidation to glycolate, glyoxylate, and oxalateOxalateOxalate , is the dianion with formula C2O42− also written 22−. Either name is often used for derivatives, such as disodium oxalate, 2C2O42−, or an ester of oxalic acid Oxalate (IUPAC: ethanedioate), is the dianion with formula C2O42− also written (COO)22−. Either...
. It is glycolate and oxalate that are primarily responsible for the metabolic acidosisMetabolic acidosisIn medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
and renal damage that are seen in ethylene glycol poisoning.
- Methanol is first metabolized to formaldehydeFormaldehydeFormaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...
and then undergoes subsequent oxidation via formaldehyde dehydrogenaseFormaldehyde dehydrogenaseIn enzymology, a formaldehyde dehydrogenase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are formaldehyde, NAD+, and H2O, whereas its 3 products are formate, NADH, and H+....
to become formic acidFormic acidFormic acid is the simplest carboxylic acid. Its chemical formula is HCOOH or HCO2H. It is an important intermediate in chemical synthesis and occurs naturally, most notably in the venom of bee and ant stings. In fact, its name comes from the Latin word for ant, formica, referring to its early...
. It is formic acid that is primarily responsible for the metabolic acidosis and visual disturbances that are associated with methanol poisoning.
- Concurrent use with ethanol is contraindicated because fomepizole is known to prolong the half-life of ethanol.
When used as an antidote in cases of methanol or ethylene glycol poisoning, fomepizole is administered by injection. Fomepizole is supplied as brand name Antizol in 1.5 mL vials containing 1500 mg of fomepizole. The cost per vial is around $1000 when purchased as a brand name product as of 2010, and therefore is not widely stocked in some hospital pharmacy stocks.
Raptor Pharmaceuticals is investigating 4-methylpyrazole as possible solution to curing "Asian Glow" or "Asian Flush" due to ALDH2
ALDH2
Aldehyde dehydrogenase 2 family , also known as ALDH2, is a human gene found on chromosome 12.-Function:The enzyme encoded by this gene belongs to the aldehyde dehydrogenase family of enzymes that catalyze the chemical transformation from acetaldehyde to acetic acid...
deficiency. The drug is currently named Convivia and has completed Phase 2a of FDA clinical trails showing that it did have success in reducing acetaldehyde
Acetaldehyde
Acetaldehyde is an organic chemical compound with the formula CH3CHO or MeCHO. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale industrially. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants as part...
levels in subjects with ALDH2 deficiency.
Absorption and distribution
Fomepizole distributes rapidly into total body water. The volume of distribution is between 0.6 and 1.02 L/kg. The therapeutic concentration is from 8.2 to 24.6 mg (100 to 300 micromoles) per liter. Peak concentration following single oral doses of 7 to 50 mg/kg of body weight occurred in 1 to 2 hours. The half-life varies with dose and therefore has not been calculated.Metabolism and elimination
Hepatic; the primary metabolite is 4-carboxypyrazole (approximately 80 to 85% of an administered dose). Other metabolites include the pyrazoles 4-hydroxymethylpyrazole and the N -glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole.Following multiple doses, fomepizole rapidly induces its own metabolism via the cytochrome P450 mixed-function oxidase system.
In healthy volunteers, 1 to 3.5% of an administered dose was excreted unchanged in the urine. The metabolites also are excreted unchanged in the urine.
Fomepizole is dialyzable
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
.