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Introduction
Fomepizole, commonly referred to a 4-methylpyrazole
or 4-MP, is a relatively recent addition to the therapeutic regimens
for ethylene glycol and methanol poisonings. Fomepizole, as either
the sulfate or hydrochloride salt, has been available in France
since 1981 through a centralized compounding pharmacy servicing
French hospitals. Until about 1990, fomepizole was used there investigationally
to treat ethylene glycol poisonings. Since 1990, fomepizole has
been accepted as the standard of care in France for the treatment
of ethylene glycol poisonings.
In 1997, Antizol (fomepizole) Injection was approved by the FDA as an antidote for ethylene glycol (antifreeze) poisoning, or for use in suspected ethylene glycol ingestion. In 2000, Antizol was approved by the FDA for an additional indication as an antidote for methanol poisoning, or for use in suspected methanol ingestion. In 2000, Antizol was approved by Health Canada as an antidote for ethylene glycol poisoning, followed by approval in 2001 as an antidote for methanol poisoning.
Chemistry
Antizol is the free base form of fomepizole,
which has a molecular formula of C4H6N2
and a molecular weight of 82.1 grams/mole. Antizol is a clear, colorless
to yellow liquid at room temperature, but may solidify below 25°
C (77° F). Solidification does not affect the efficacy, safety,
or stability of Antizol [Antizol (fomepizole) Injection package
insert]. Its chemical structure is shown in Figure 3.
Figure 3. Chemical Structure of Antizol
Mechanism of Action
Antizol is a competitive inhibitor of alcohol dehydrogenase, the
enzyme that catalyzes the oxidation of ethanol to acetaldehyde.
Alcohol dehydrogenase also catalyzes the initial steps in the metabolism
of ethylene glycol and methanol to their toxic metabolites.
Absorption, Bioavailability
and Distribution
Intended for administration by the intravenous route, Antizol is
immediately and completely bioavailable. Antizol rapidly distributes
to total body water. The volume of distribution is between 0.6 L/kg
and 1.02 L/kg [Antizol (fomepizole) Injection package insert].
Metabolism and Excretion
In healthy volunteers, only 1-3.5% of an administered dose of Antizol
(7-20 mg/kg oral and IV) was excreted unchanged in the urine, indicating
that metabolism is the major route of elimination (Jacobsen 1990).
In humans, the primary metabolite of Antizol is 4-carboxypyrazole
(4-CP), which is excreted in the urine.
Other minor metabolites of fomepizole observed
in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates
of 4-carboxypyrazole and 4-hydroxymethylpyrazole. These metabolites
are either inactive or are so weakly active
(4-hydroxymethylpyrazole) that they do not contribute significantly
to the inhibition of alcohol dehydrogenase (Weintraub 1988).
The elimination of Antizol is enhanced after several
doses have been administered at 12-hour intervals, suggesting that it induces its own metabolism.
Following auto-induction, a first order kinetic model more closely
describes the elimination of Antizol. The metabolism of Antizol
to 4-CP occurs after an initial cytochrome P-450-mediated hydroxylation
followed by further oxidation. As antizol is a potent inducer of
cytochrome P-450-mediated drug elimination in animal studies, the
auto-induction of Antizol elimination in humans over 36-48 hours
may also involve the induction of cytochrome P-450 (Jacobsen 1990).
The elimination of Antizol follows zero order,
saturable Michaelis-Menten kinetics after acute doses and a first
order kinetic model after induction of metabolism following chronic
doses. Values for plasma half-life vary with dose and were therefore
not calculated in early study reports.
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