Background: In Australasia methanol overdoses are treated with high doses of ethanol. Appropriate dosing recommendations are lacking and in some cases dosing of ethanol is inadequate. There are no models for ethanol pharmacokinetics in the presence of methanol available in the literature. Aim: The overall aim is to develop dosing guidelines for ethanol treatment of methanol intoxication. The specific aim of this part of the project is to develop a pharmacokinetic model of ethanol in the presence of methanol.
Methods: Concentration-time data were available for a patient who ingested methanol and was treated with ethanol. The dose of methanol was estimated to be 166 g. The ethanol dose consumed by the patient immediately prior to methanol intoxication was not recorded. The patient was treated with both oral and intravenous ethanol combined with continuous veno-venous haemodialysis (CVVHD). Thirty three methanol and forty ethanol blood concentrations were taken. The data was then modelled using NONMEM VI.
Results: A model combining both ethanol and methanol including a competitive interaction for the enzyme alcohol dehydrogenase was developed. It was found that methanol was best described by a one compartment mixed linear and Michaelis-Menten model to which CVVHD increased the clearance by 70%. Ethanol was described by a one compartment model with combined linear and Michaelis-Menten kinetics with the initial patient instigated dose-rate estimated. The combined model accounted for a two way competitive interaction between methanol and ethanol with alcohol dehydrogenase. CVVHD increased the linear component of ethanol clearance by approximately 21%. The affinity of Methanol for alcohol dehydrogenase was 18-fold less than that for ethanol. The half-life of methanol in the presence of ethanol and CVVHD was 13.5 hours, while it was 23 hours in the absence of CVVHD.
Conclusions: Methanol appears to decrease the affinity of ethanol for metabolic processes. CVVHD appears to have a significant effect at increasing clearance of methanol and to a lesser extent ethanol. Despite the presence of a significant competitive interaction between methanol and ethanol for alcohol dehydrogenase there was no apparent nonlinearity seen with methanol suggesting that its elimination in the presence of ethanol is predominantly renal.