Ethanol pharmacokinetics in white women: Nonlinear model fitting versus zero-order elimination analyses

Background: Studies have shown repeatedly that ethanol pharmacokinetics are not linear, yet most researchers still determine ethanol elimination by li near, zero-order kinetics. The goals of the present work were to: (1) fit f our nonlinear pharmacokinetic models to mean breath alcohol concentration ( BrAC)-time data of 27 women and determine the best-fit model; (2) fit the d etermined best-fit model to individual BrAC data and estimate the pharmacok inetic parameters; and (3) compare the method of nonlinear model fitting wi th the classical zero-order elimination method and determine in which cases the classical approach is justified. Methods: Twenty-seven healthy white women ingested four drinks (total of 0. 67 g.kg(-1)) of ethanol on two test days. Approximately 24 breath ethanol s amples (for pharmacokinetic analyses) and one blood sample (for hormonal ma rkers) were taken per day. Pharmacokinetic model evaluation was based on th e coefficient of variation, the weighted residual sum of squares, and the s equence of the weighted residuals. Because hormonal changes across the mens trual cycle did not significantly influence ethanol pharmacokinetics, data from the two test days were pooled. Results: The best-fit model was a one-compartment open model with first-ord er absorption and sequential first-order elimination, followed by Michaelis -Menten elimination kinetics. Fitting this model to the individual BrAC dat a yielded mean k(a) = 0.062 hr(-1), V-d = 0.457 L.kg(-1), k(e) = 0.011 hr(- 1), V-max = 0.136 g.L-1.hr(-1), and K-m = 0.096 g.L-1. For the classical an alyses, mean time to peak BrAC = 1.83 hr, disappearance rate = 0.179 g.L-1. hr(-1), and area under the blood ethanol-time curve (AUC) = 2.884 g.L-1.hr. Correlational analyses showed that more frequent drinkers eliminated ethan ol significantly faster and reached significantly lower AUC than less frequ ent drinkers. Conclusions: After multiple dose ingestion in white women, classical zero-o rder elimination analyses can be applied only to a limited portion of the d escending BrAC-time curve. They seem justified and practical from 0.5 hr af ter peak BrAC until BrAC reaches 0.2 g.L-1. To describe ethanol pharmacokin etics across the entire BrAC-time curve, however, sophisticated nonlinear m odel fitting is required.