Metabolism

The first step of methanol metabolism is the oxidation to formaldehyde by alcohol dehydrogenase (ADH). Formaldehyde is then metabolised by the specific enzyme formaldehyde dehydrogenase. In this reaction formaldehyde combines with reduced glutathione to form s-formyl glutathione. This hydrolyses to produce formic acid and glutathione. Formaldehyde oxidation occurs in the erythrocytes and in liver mitochondria. Due to the numerous metabolic routes, all formaldehyde is metabolised to the toxic formic acid (Liesivuori and Savolainen, 1991) and it is not seen to accumulate in methanol intoxication.

Formaldehyde may also be metabolised to formic acid via a tetrahydrofolic acid-dependent one-carbon pool. Formic acid binds to tetrahydrofolic acid (THF) to form 10-formyl-THF. Various other enzymatic reactions direct 10-formyl-THF to other pathways. In rats, formic acid is metabolised at about twice the rate of monkeys (McMartin et al., 1977). However, hepatic THF levels in humans and monkeys are about half that seen in rats, and formylated-THF derivatives are 2-fold higher in monkeys than rats. Consequently, low hepatic concentrations of THF in humans and monkeys may lead to an accumulation of formic acid.

Cases have been reported where ingestion of methanol has not resulted in acidosis, even in the absence of ethanol therapy. A 6 week old infant was accidentally fed a methanol containing windshield fluid mixed in infant formula. On discovery of the mistake the patient was immediately taken to hospital and a nasogastric lavage was performed. Apart from tachypnoea, which resolved within 3 hours of ingestion, there were no abnormal signs. A blood concentration taken 2 hours post ingestion showed a methanol concentration of 456 mg/l. A subsequent methanol concentration suggested a half-life of 28 hours and a clearance rate of 8.8 mg/l/ hour. In this case, low alcohol dehydrogenase levels in infants may have slowed the rate of methanol metabolism and therefore slowed the generation of toxic metabolites, reducing the risk of sequelae (Brent et al., 1991).

Toxicology of Solvents Elimination

In cases of human toxicity, the kinetics of methanol elimination have been difficult to determine, as the standard treatment with ethanol and haemodialysis alter the kinetics. Studies in monkeys suggest that the kinetics of methanol elimination are zero-order at blood concentrations in the range 1,000-2,000 mg/l, i.e., at levels normally reported in human toxicity (Noker et al., 1980). However, McMartin et al. (1977) found that methanol elimination followed first-order kinetics in a monkey receiving large doses of methanol (3 g/kg). The mixed kinetics may be due to the greater contribution of first-order processes (urinary and pulmonary clearance) to the whole body clearance of methanol (Jacobsen et al., 1988).

During haemodialysis of a patient who had ingested methanol, the average half-life of methanol and formic acid were 3.5 hours and 45 minutes, respectively. The half-life of methanol when not having dialysis was calculated at 15.1 hours (Barton-Burns et al., 1998). In some studies, the methanol elimination half-life is long. Brent et al. (1991) found that the methanol elimination half-life in a 6 week old child was 28 hours, but this may be due to reduced alcohol dehydrogenase levels in neonates. The half-life of methanol appears to be variable in the range 2-54 hours (Barton-Burns et al., 1998; Baselt, 2000; Brent et al., 2001).

Formic acid, the metabolite responsible for the majority of toxic effects following methanol exposure, appears to be cleared less quickly from ocular tissue when compared with systemic clearance (Garner et al., 1995).

Only a small quantity of methanol (<1%) is excreted unchanged in the urine (Dutkiewicz et al., 1980; Kawai et al., 1991).

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