Alcohol abuse and alcoholism are responsible for a wide variety of medical problems. The pharmaco-therapeutic aspect of alcoholism includes the use of drugs, with different actions and objectives. Among them, metadoxine seems to-be of interest. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, to help restore the functional structure of the liver and to relieve neuro-psychological disorders associated with alcohol intoxication. Metadoxine also seems to be safe; in more than 15 years of post-marketing surveillance only minor a specific and reversible events were monitored in patients exposed to the treatment. In this review the preclinical and clinical results obtained using metadoxine in acute and chronic alcohol intoxication are reported.
Alcoholism is a multifactorial disorder in which biologic and genetic factor interact along with cultural and social factors (1,2). Alcohol addiction represents a social problem and a relatively common disease of western countries like Europe and the USA. From 20 to 40% of subjects admitted to hospitals have alcohol-related problems (3) and in elderly people alcohol-related disorders represent as frequent a reason for hospitalization as myocardial infarction (4).
The most lasting damaging actions of ethanol are exerted on the liver function and structure (5). A liver disease is often present in patients affected by alcohol abuse and/or alcoholism; however the mechanisms responsible for the liver toxicity of ethanol are still not completely understood (6).
Ethanol also modifies the GABA-mediated neurotransrnission (7). Probably it preferentially Stimulates the dopaminergic transmission in the mesolimbic system (8), interferes with serotoninergic transmission (9) and with the release of glutamate in the central synapses (10), The neuropathological manifestations usually appear after many years of excessive drinking. In addition to the effects of alcohol on the nervous system, it may be one of the
major contributing factors to road accidents, suicide and violent death in young adults (11).
The pharmaco-therapeutic aspect of alcoholism
includes the use of drugs, with different actions and
objectives (12). Among them, metadoxine seems to
be of interest. The present review evaluates the
pharmacology and the therapeutic use of metadoxine
(figure 1), a drug promoted for the treatment of acute
and chronic alcohol intoxication and alcoholic liver
disease.
Enzymatic activity of Metadoxine compounds Metadoxine is formed by the salification of two components, pyrrolidone carboxylic acid (PCA) and pyridoxol, in a single product. PCA is usually present in the diet and produced endogenously by enzymatic conversion of the gammaglutamyl amino acids to PCA and free amino acids in several mammalian tissues, including the central nervous system, where it has a role in the composition of neuroacti ve molecules (13). PCA is an intermediate in the gammaglutamyl cycle, it is transformed into glutathione by two subsequent reactions catalyzed by gamma-glutamyl cysteine synthetase and glutathion synthetase
respectively, and its production is linked to the gammaglutamyl transferase activity of the liver cell membrane and to hepatic levels of reduced glutathione (GSH) (14). It has also been shown that PCA facilitates ATP synthesis by stimulating the "denovo" synthesis of the purine nucleotide. (15). Pyridoxol is a precursor of coenzymes such as pyridoxal phosphate which accelerates the metabolic degradation of ethanol and prevents ATP inactivation by acetaldehyde, the main ethanol metabolite (16).
In Metadoxine PCA and Pyridoxol are linked by salification and in this form their pharmacological properties seem to be synergic as shown by their superior activity when given together, with respect to separate administration (17,18).
Pharmacokinetic profile Metadoxine exerts a metabolic effect, the efficiencies of which depend on the presence of both moieties, pyridoxine (PDX) and pyrrolidone carboxylate (PCA); in the same tissue with the same profile, and both in concentrations able to trigger the metabolic biotransformations in which they are implicated. Pharmacokinetic studies have been performed in rats, dogs, monkey and healthy volunteers (18-20). These studies mainly showed that the oral absorption of the drug is fast, with high and reproductive absolute bioavailability (60 to 80%) and with extensive tissue distribution, as shown by the large apparent distribution volume. The half-life is 40 to 60 minutes without appreciable differences between oral or intravenous administration. The kinetic profile is specific to metadoxine as such. The extemporaneous administration of the two individual components can not compete in terms of the blood concentration, thus of tissue distribution and ultimately of therapeutic-effect, with Metadoxine.
β’ This is the consequence of Metadoxine being an ion-pair, and was very easily seen comparing the kinetic profile of pyridoxine administered as a component of Metadoxine, with that of the same pyridoxine administered alone (21), which yields lower concentrations with a very long delay.
The identified metabolites are those expected from the metabolism of glutamate and of pyridoxine. In particular, the radioactivity given with metadoxine was found in glutamate, glutamine, glutamylcysteme, glutathione, a-ketog!utarate, pyridoxal, pyridoxal phosphate and pyridoxamine. Approximately 12% of total radioactivity was found in peptide derivatives,
probably synthesised via the g-glutamil cycle, (21). Excretion occurs approxi mately in the same proportion through the urine and the feces, between 40 and 45% in 24 hours in the urine, and between 35 and 50% in 96 hours in the feces (21). This information justifies the dosage scheme recommended tor the therapeutic use in humans.
Preclinical studies
Metadoxine has been shown to induce profound alterations of alcohol metabolism in rats. It increases the activity of acetaldehyde dehydrogenase and prevents the decrease in alcohol dehydrogenase activity shown in chronic ethanol fed rats (22,23). Its administration accelerates plasma and urinary clearance of ethanol and acetaldehyde in a dose-dependent manner (22). The accelerated urinary clearance could be due to the inhibiting effect of metadoxine on the formation of macroaggregates between albumin and acetaldehyde shown in alcohol treated rats. Metadoxine significantly inhibits the increase of fatty acid esters in the liver of ethanol treated rats (24), restoring the correct ratio between hepatic saturated and unsaturated fatty substances (25). At 160 mg/kg, Metadoxine also prevented the formation of fatty liver in 50% of rats exposed to a dose of ethanol able to induce fatty liver in 100% of the rats in the control group (23).
In normal untreated rats, Metadoxine has been
shown to increase hepatic ATP content through an
activation of the purine "denovo" synthesis (15,17),
and in hepatocytes of acutely and chronically alcohol
intoxicated rats it is able to restore the activity of the
aldehyde dehydrogenase and to increase the reduced
glutathione levels (26). Pretreatment of animals with
Meladoxine one hour before ethanol administration
produced significant protection against glutathione
depletion and oxidoreductive stress in hepatic and
extrahepatic tissue (27,28), and an increment in alcohol
metabolism and turnover (25). Recently Metadoxine
has been shown to prevent glutathione depletion,
lipid peroxidation damage, collagen deposition and
TNF alfa secretions induced by alcohol and
acetaldehyde in hepatocytes and hepatic stellate cells
(29) These mechanisms could be implicated in the
ability of Metadoxine to prevent hepatic
necroinflammation, fibrosis and progression to
cirrhosis in rats chronically exposed to hepatotoxic
agents as shown in rat models of hepatic cirrhosis.