Plasma and tissue determination of 4-methylpyrazole for pharmacokinetic analysis in acute adult and pediatric methanol/ethylene glycol poisoning

Abstract

Methanol and ethylene glycol poisoning may result in severe intoxication. The inhibition of alcohol dehydrogenase by ethanol or 4-methylpyrazole (4-MP, fomepizole) is fundamental to their treatment. 4-MP presents several advantages over ethanol therapy and has been recently approved as a specific antidote for both intoxications. The authors have developed a simple gas chromatographic method to determine blood and tissue 4-MP concentrations. This method has been validated for its reproducibility (between-day CV < 6.3%), sensitivity (LOD 0.2 microg/mL), and linearity. It has been used in 4 adult patients intoxicated by methanol and 1 child accidentally intoxicated by ethylene glycol. 4-MP was used for each patient, and its blood levels were monitored every 4 hours over 2-3 days for pharmacokinetics purposes. In the population studied, after repeated administration of 10 mg/kg fomepizole, plasma 4-MP concentrations ranged from 1.4 to 21.6 microg/mL, always above the active level of 0.8 microg/mL. The mean peak concentration observed in the 4 adult patients was 18.5 +/- 2.6 microg/mL and in the child was 18.9 +/- 2.2 microg/mL. Even though 4-MP is characterized by a dose-dependent kinetic profile, under our conditions of dosage and blood sampling, its elimination better fitted a first-order kinetic model. At steady state and without any concomitant therapies, the mean apparent elimination half-life was 14.5 +/- 3 hours. Elimination seemed faster in the child. A trend toward a progessive enhancement of the 4-MP elimination rate is suggested in the pediatric case, with the duration of the treatment resulting in a t(1/2) below 5 hours after 48 hours. One patient died, and samples of blood and hepatic tissue were removed simultaneously during autopsy for 4-MP analysis. Interestingly, when the plasma concentration was subtherapeutic (<1 microg/mL) the tissue concentration observed was still significant with 12 microg/g, supporting an intermittent scheme of administration.