Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. For the Methylpyrazole for Toxic Alcohols Study Group.
The elimination kinetics of ethylene glycol (EG) in human subjects treated with fomepizole (4-methylpyrazole) were analyzed to establish the efficacy of alcohol dehydrogenase (ADH) inhibition and to characterize elimination pathways.



Drug concentration data from patients enrolled in the EG arm of the Methylpyrazole for Toxic Alcohols trial, a prospective, multicenter, open-label trial of fomepizole, were analyzed and compared with published estimates.



In 19 patients analyzed (EG concentrations of 3.5 to 211 mg/dL), elimination was first order during fomepizole monotherapy (half-life of 19.7+/-1.3 hours) and was not affected by the presence of ethanol. The elimination rate was significantly faster (half-life of <8.6+/-1.1 hours, P <.001) in the absence of fomepizole and ethanol. EG elimination by the kidneys was directly proportional to remaining renal function as estimated by creatinine clearance, with a fractional excretion of 25.5%+/-9.4%. Renal elimination and hemodialysis were the only significant routes of EG elimination as long as fomepizole concentrations were maintained well above 10 micromol/L (EG/fomepizole molar ratio, <100:1). All patients with normal serum creatinine concentrations at the initiation of fomepizole treatment had rapid rates of renal elimination (half-life of 16.8+/-0.8 hours).



At doses used, fomepizole effectively inhibits ADH-mediated metabolism of EG. Serum creatinine concentration at presentation and creatinine clearance can be used to predict EG elimination during fomepizole therapy and can help determine which patients will require hemodialysis to expedite EG elimination. An absolute EG concentration above 50 mg/dL should no longer be used as an independent criterion for hemodialysis in patients treated with fomepizole.
Sivilotti
M L
ML
University of Massachusetts Medical School, Worcester, MA, USA. msivilotti@ottawahospital.on.ca
Burns
M J
MJ
McMartin
K E
KE
Brent
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000426:Alcohol Dehydrogenase / Q000187:drug effects*; D000435:Alcoholic Intoxication / Q000628:therapy*; D000931:Antidotes / Q000008:administration & dosage*; D003401:Creatine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004636:Emergency Service, Hospital; D019855:Ethylene Glycol / Q000493:pharmacokinetics* / Q000506:poisoning*; D005260:Female; D000077604:Fomepizole; D006801:Humans; D007275:Injections, Intravenous; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D011336:Probability; D011720:Pyrazoles / Q000008:administration & dosage*; D006435:Renal Dialysis; D016896:Treatment Outcome
D000931:Antidotes; D011720:Pyrazoles; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; D019855:Ethylene Glycol; D003401:Creatine