Chronopharmacokinetics of ethanol. I. Review of the literature and theoretical considerations.

Pharmacokinetic parameters are generally assumed to be invariate with the time of day, although circadian variation of drug metabolism and drug response is known. As proposed, chronopharmacokinetics considers the implications of the chronovariability of pharmacokinetic parameters. In order to investigate chronovariation in the rate of disappearance of a substance from the approximate a linear course until very low blood levels are attained. As a background for such studies, the literature on the chronopharmacologyof ethanol and the pharmacokinetics of ethanolemia is reviewed. Theoretical considerations are presented for chronovariation of elimination constants for hypothetical drugs following exponential and zero-order models. In describing these cases, the substitution of a sinusoidal function for the rate-constants in pharmacokinetic differential equations is proposed and graphed herin for the first time. It is concluded that: 1)rhythmicity within elimination curves can only be determined by repetion of the experiment at different times of the diel period; 2)the expectation that a rate-constant estimated at one time of the day may be valid for another part of the day carries with it an unknown risk. No pharmacokinetic analysis can be considered definitive unless chronopharmacokinetic variation of parameters is considered.