(744f) Dynamic Treatment Strategies for Methanol Intoxication Using Ethanol As Alcohol Dehydrogenase Inhibitor in Human Beings

Methanol poisoning is a fatal public health problem that affects population in both developed and developing countries particularly as alcohol consumption increases in most countries around the world. Several sources of poisoning are related to this issue (e.g. adulterated beverages, inappropriate distillation processes, methylated spirits, accidental exposure to this organic solvent, suicide attempt cases, among others). The inlet routes to the systemic metabolism are usually ingestion, inhalation or absorption through the skin. Several isolated cases of mass intoxications have taken place worldwide in recent years, Nicaragua (788 cases, 2006); Colombia (31 cases, 1989 and 88 cases, 2004); Jordan (17 cases 2006), Estonia (154 cases, 2001) [1-6]. Nevertheless, the total of cases per year in each country might be higher: Colombia (136 cases, 2007 and 250 cases, 2008); United States (2283 possible cases, 2007) [7].

 Methanol toxicity arises due to two main accepted mechanisms: i) central nervous system depression and ii) biotransformation of methanol into formaldehyde and then to formic acid. Therefore, current treatments approaches are related to alcohol dehydrogenase (ADH) inhibition, since this enzyme is the one responsible for methanol metabolism to formaldehyde (the toxic metabolite). In emergency settings and with the purpose of treating patients for Methanol poisoning, inhibition is carried out using intravenous injection of “pure” ethanol or 4-methylpirazole (fomepizole) because these compounds may compete for the active sites on the ADH enzyme.

Several in-silico models for alcohols and glycols have been developed and the physiologically based pharmacokinetic (PBPK) ones are the most common because these enhance the fitting with experimental data keeping the physiological meaning of each differential equation [7-8]. Nevertheless, in the state of art there are few models that include non-reactive elimination pathways or dynamic control strategies in order to provide the most accurate doses for the inhibition kinetics of ADH in a physiological media.

In this study a multi-compartment physiologically based pharmacokinetic model including non-reactive elimination pathways, and a dynamic optimization technique is implemented in order to minimize the formaldehyde production on the alcohol dehydrogenase ADH enzyme using intra-venous ethanol as inhibitor. This technique is contrasted with a PID control strategy designed to stabilize the vein formaldehyde concentration under critical levels, the controller parameters are tuned up via nonlinear optimization techniques. 

The proposed PBPK model includes separation between venous and arterial blood pools, and the main organs for methanol, ethanol and its metabolites biodistribution have been modeled in detail (i.e. Liver, lungs, kidneys, muscles and fat, stomach, gastrointestinal tract and skin), and the reactive unit (liver) is modeled as series of CSTR reactors with a reversible Michaelis-Menten kinetics. Additionally, the parameters for this model have been adjusted and validated using experimental data from the literature.

Keywords: Methanol intoxication, enzymatic inhibition, dynamic optimization, PID control.

References:

 

[1] Pan American Health Organization, Methanol Poisoning in Leon, Nicaragua, Report, September, (2006).

[2] Bennett I.L., Cary F.H., Mitchell G.L., et al., Acute methyl alcohol poisoning: A review based on experiences in an outbreak of 323 cases. Medicine 32:431-463, (1953).

[3] Kane R.L., Talbert W., Harlan J., et al., A methanol poisoning outbreak in Kentucky. A clinical epidemiologic study In Archives of Environmental Health, 17(1):119-29. (1968).

[4] Paasma R., Hovda K.E., Tikkerberi A., Jacobsen D., Methanol mass poisoning in Estonia: outbreak in 154 patients. Clin Toxicol (Phila). 45(2):152-7 (2007).

[5] Balaguer J., Intoxicación por Metanol. Toxicología Clínica. Bataller Editorial, Published in Spain p. 60-64 (2004).

[6] Colombian National Health Institute, Methanol monitoring and poisoning control (2010).  (Original language: Protocolo de vigilancia y control de intoxicaciones por metanol, Instituto nacional de salud de Colombia (2010)).

[7] BrentJ. Fomepizole for Ethylene Glycol and Methanol Poisoning. The new england journal of medicine 360; 21 may 21, 2009