Repetitive administration at constant time intervals of fixed doses of drugs which are eliminated by apparent first-order kinetics will usually result in the eventual attainment of a drug level plateau in the body. If a drug is eliminated solely by capacity-limited (Michaelis-Menten) kinetics in the therapeutic dose range, it will accumulate in the body without limit when the dose exceeds a certain amount. Drugs eliminated by parallel apparent first-order and capacity-limited kinetics will attain a drug level plateau but, unlike drugs eliminated only by first-order kinetics, the ratio of plateau level-dose is not independent of dose but increases with increasing dose. The rate of this increase is particularly high in a certain dose range which, therefore, represents a “danger zone” in which an increase in dose causes a considerably more than proportional increase in plateau level. This may be the cause of some adverse and toxic effects of certain drugs, such as the salicylates, during chronic therapy.
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