Do Ethanol and Deuterium Oxide Distribute Into the Same Water Space in Healthy Volunteers?

Abstract

Background: The volume of distribution at steady state for ethanol (V ss ) is thought to be identical to the total body water (TBW). We compared a two-compartment pharmacokinetic model with parallel Michaelis-Menten and first-order renal elimination with the classical one-compartment zero-order elimination model. Ethanol concentration-time profiles were established for breath, venous blood, and urine. The values of V ss obtained for ethanol were compared with TBW determined by deuterium oxide dilution.Methods: Sixteen healthy volunteers each received a 30-min intravenous infusion of ethanol on two occasions. Ethanol was measured in breath by a quantitative infrared analyzer and in blood and urine by headspace gas chromatography. Deuterium oxide was given as an intravenous injection and measured in serum by isotope-ratio mass spectrometry. Components of variation were calculated by ANOVA to determine the precision of the estimates of V ss and TBW.Results: Mean TBW, determined by deuterium oxide dilution, was 44.1 Ϯ 3.9 liters (ϮSD) for men, corresponding to 0.61 liters/kg, and 37.4 Ϯ 3.2 liters for women, or 0.54 liters/kg. Estimates of V ss from blood-ethanol pharmacokinetics were 87.6% of TBW according to isotope dilution and 84.4% for breath analysis with the two-compartment model. This compares with 95.1% and 95.4% for blood and breath alcohol, respectively, when the classical zero-order kinetic analysis is used. The precision of the estimates of V ss and TBW was between Ϯ1.56 and Ϯ2.19 liters (95% confidence interval).Conclusions: Ethanol does not distribute uniformly into the TBW. The precision of measuring V ss by ethanol dilution was comparable to estimates of TBW by isotope dilution. Results of noninvasive breath ethanol analysis compared well with use of venous blood for estimating V ss . The sophisticated twocompartment model was much superior to the classical one-compartment model in explaining the total concentration-time course of intravenously given ethanol.

PKQuest: measurement of intestinal absorption and first pass metabolism – application to human ethanol pharmacokinetics

“…The recent measurements of Norberg et al[16] of the time course of ethanol blood levels after an IV input were used to determine the standard ethanol PBPK parameters. PKQuest was used to model the time course of the mean blood values of the 16 subjects (8 men, 8 women).…”

“…Comparison of the time course of the ethanol arterial blood water concentration (solid line) and the experimental results of Norberg et al [16]. …”

“…A baseline ethanol PBPK model was developed based on the careful and detailed measurements of Norberg et al [16] of the simultaneous breath and venous blood concentrations for a 30 minute constant IV ethanol infusion. The concentration calculated from the breath measurements was in good agreement with the direct venous measurements.…”

“…The total body water for each subject in this study was directly measured using D 2 O. The time course of the mean values for all 16 subjects (figure 1, [16]) was modeled using PKQuest. The data of DiPadova et al [17] was used for the determination of the rate of absorption of oral ethanol, along with calculations of the PA and FPM.…”

Must hypervolaemia be avoided? A critique of the evidence

“…Although in the 1980s [30], as well as later [31], I personally worked with tracers to estimate body fluid volumes, I try to refrain from using them as they are subject to a host of potential errors, some of which may not even be realised today. As an alternative, I have developed volume kinetics as a robust alternative method for studying the behaviour of infusion fluids in the living human body.…”