Altering ethanol pharmacokinetics to treat alcohol use disorder: Can you teach an old dog new tricks?

Abstract

Disulfiram was the first pharmacotherapy approved to treat alcohol use disorder in the 1950s. Disulfiram alters ethanol pharmacokinetics and causes uncomfortable reactions (e.g. headache, tachycardia, nausea, flushing and hypotension) when alcohol is consumed. Subsequently, a better understanding of the neurobiological pathways involved in alcohol use disorder led to the development of other medications (e.g. naltrexone and acamprosate). These neurobiological-based medications act on alcohol use disorder-related phenotypes including craving, stress, and/or withdrawal. The original approach to treat alcohol use disorder, by altering ethanol pharmacokinetics has been much less investigated. Recent research on ethanol pharmacokinetics has shed light on the mechanisms of action underlying alcohol use disorder and how some medications that alter ethanol pharmacokinetics may be helpful in treating alcohol use disorder. This review summarizes and discusses the complex pharmacokinetics of ethanol, and proposes that altering ethanol pharmacokinetics via novel pharmacological approaches may be a viable approach to treat alcohol use disorder.

Keywords: Pharmacokinetics; alcohol use disorder; biobehavioral mechanisms; ethanol; human laboratory studies.

Figure 1. Pharmacological approaches that target ethanol metabolism via ALDH inhibition

Non selective irreversible inhibition of ALDH (disulfiram) produces aversive side-effects. Selective ALDH2 reversible inhibition (ALDH2i) has been shown to prevent the increase of alcohol-induced rewarding dopamine release in brain, reduce cocaine-induced euphoria and inhibit anxiety-like behaviors.

Figure 2. Pharmacological approaches that can reduce ethanol cytotoxic effects

The pyridoxine-pyrrolidone carboxylate metadoxine can accelerate ethanol metabolism by increasing the activity of ALDH, inhibiting CYP2E1, and accelerating plasma and urinary clearance of ethanol. Metadoxine may also reduce cytotoxic effect of ethanol, reduce intoxication and improve recovery.

Figure 3. Pharmacological approaches that target the biphasic effects of ethanol

The α₂-adrenergic antagonist idazoxan can reduce subjective effects secondary to ethanol intoxication.