Contribution of liver alcohol dehydrogenase to metabolism of alcohols in rats.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro enzymatic and in vivo animal pharmacokinetic study
PubMed 25641189 · doi:10.1016/j.cbi.2014.12.040
What was done
Purified rat liver alcohol dehydrogenase (ADH) oxidation kinetics were determined in vitro (pH 7.3, 37 °C) and compared with in vivo elimination kinetics in rats across primary alcohols, secondary alcohols, and diols (doses 5–20 mmol/kg). To evaluate the specific contribution of ADH, elimination rates were also measured following inhibition with 1 mmol/kg 4-methylpyrazole.
What was found
Primary alcohols and diols were eliminated via zero-order kinetics (5–20 mmol/kg), with ethanol showing the fastest elimination rate at 7.9 mmol/kg/h. Secondary alcohols were eliminated via first-order kinetics (5–10 mmol/kg) to corresponding ketones. Treatment with 4-methylpyrazole inhibited elimination across alcohols by an average of 73% (ranging from 55% for 2-propanol to 90% for ethanol). In vivo elimination rates plateaued at a maximum of 6±1 mmol/kg/h for the most efficient substrates, despite higher predicted turnover from in vitro kinetics.
Why it matters
This study quantifies the proportional role of ADH in the systemic clearance of various primary, secondary, and diol alcohols in rats. It establishes that while ADH is the predominant metabolic pathway, systemic clearance hits an upper velocity ceiling, indicating unidentified physiological or metabolic rate-limiting factors beyond NADH reoxidation.
Limits
The study was conducted entirely in rats and in vitro systems, limiting direct extrapolation to human pharmacokinetics. The abstract does not report the total number of animals (n), precise sample sizes per compound, or error margins for most kinetic values.
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