Magnitude and Time-Course of Arterio-Venous Differences in Blood-Alcohol Concentration in Healthy Men

Abstract

Human studies of arterio-venous (AV) differences in drug concentrations and the consequences for pharmacokinetic modelling and concentration-effect relationships are very limited. We therefore investigated the intravenous and intra-arterial concentrations of alcohol (ethanol) during the absorption, distribution and elimination stages of alcohol metabolism in healthy men. Nine male volunteers aged 26-67 years drank 0.6 g alcohol/kg bodyweight in 2-15 minutes. The drink was prepared from 95% v/v alcohol, which was diluted with an alcohol-free beverage to 20% v/v. Before the start of drinking and for 6-7 hours post-administration, blood samples were drawn at 15- to 20-minute intervals from indwelling catheters in a radial artery and a cubital vein on the same arm. The blood-alcohol concentration (BAC) was determined by headspace gas chromatography, and blood-water content was measured by desiccation. The peak concentration (Cmax) of alcohol in arterial blood was 0.98 g/L (SD 0.209) compared with 0.84 g/L (SD 0.176) for venous blood (p < 0.001), whereas median time to reach Cmax (tmax) was the same (35 minutes). The AV difference was greatest at 10 minutes after the end of drinking (mean 0.20 g/L [range 0.09-0.40 g/L]), decreasing as the absorption of alcohol continued. At a median time of 90 minutes post-administration (range 45-105 minutes), the AV difference was momentarily zero. At later times, the AV differences became increasingly negative and at 280 minutes post-administration the mean was -0.051 g/L (range -0.025 to -0.078 g/L). The slope of the post-absorptive phase (k0) was 0.116 g/L/h (SD 0.0167) for arterial blood compared with 0.109 g/L/h (SD 0.0185) for venous blood (p < 0.001). The extrapolated time to reach zero BAC was 391 minutes (SD 34) for arterial blood and 420 minutes (SD 41) for venous blood; the difference of 29 minutes was statistically highly significant (p < 0.001). The apparent volume of distribution of alcohol, the area under the concentration-time curves (AUC) and the water content of arterial and venous blood samples were not significantly different for the two sampling compartments. The arterial and venous blood-alcohol profiles were shifted in time owing to the time it takes for alcohol to equilibrate between arterial blood and tissue water. Alcohol is metabolised in the liver but not in muscle tissue, which acts as a reservoir for alcohol. The concentrations of alcohol in arterial and venous blood were the same at only one timepoint, which signifies complete equilibration of alcohol in total body water. During the entire post-absorptive phase, the concentration of alcohol in venous blood draining skeletal muscles was slightly greater than the arterial blood concentration; therefore, the AV differences were negative.