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 linear, zero-order kinetics. The goals of the present work were to: (1) fit four nonlinear pharmacokinetic models to mean breath alcohol concentration (BrAC)-time data of 27 women and determine the best-fit model; (2) fit the determined best-fit model to individual BrAC data and estimate the pharmacokinetic parameters; and (3) compare the method of nonlinear model fitting with 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 x kg(-1)) of ethanol on two test days. Approximately 24 breath ethanol samples (for pharmacokinetic analyses) and one blood sample (for hormonal markers) were taken per day. Pharmacokinetic model evaluation was based on the coefficient of variation, the weighted residual sum of squares, and the sequence of the weighted residuals. Because hormonal changes across the menstrual 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-order absorption and sequential first-order elimination, followed by Michaelis-Menten elimination kinetics. Fitting this model to the individual BrAC data yielded mean ka = 0.062 hr(-1), Vd = 0.457 L x kg(-1), ke = 0.011 hr(-1), Vmax = 0.136 g x L(-1) x hr(-1), and Km = 0.096 g x L(-1). For the classical analyses, mean time to peak BrAC = 1.83 hr, disappearance rate = 0.179 g x L(-1) x hr(-1), and area under the blood ethanol-time curve (AUC) = 2.884 g x L(-1) x hr. Correlational analyses showed that more frequent drinkers eliminated ethanol significantly faster and reached significantly lower AUC than less frequent drinkers.


CONCLUSIONS
After multiple dose ingestion in white women, classical zero-order elimination analyses can be applied only to a limited portion of the descending BrAC-time curve. They seem justified and practical from 0.5 hr after peak BrAC until BrAC reaches 0.2 g x L(-1). To describe ethanol pharmacokinetics across the entire BrAC-time curve, however, sophisticated nonlinear model fitting is required.
Mumenthaler
M S
MS
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, CA 94305-5550, USA. msm@stanford.edu
Taylor
J L
JL
Yesavage
J A
JA
D000328:Adult; D000428:Alcohol Drinking / Q000378:metabolism*; D019540:Area Under Curve; D001944:Breath Tests / Q000379:methods; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics*; D000431:Ethanol / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008597:Menstrual Cycle / Q000378:metabolism; D017711:Nonlinear Dynamics; D044465:White People
D002492:Central Nervous System Depressants; D000431:Ethanol