Peak drug levels in linear pharmacokinetic systems—II. Conditions for a paradoxical injection rate effect with rectangular input

Abstract

The preceding paper (Thorn, 1981) has shown that in a linear pharmacokinetic system with a multimodal impulse response the peak drug level may sometimes be smaller with slower rates of injection. This paper presents two theorems on this paradoxical injection rate effect where the injection is a constant infusion of finite duration. The first theorem establishes a graphical method for determining whether a given impulse response will give a paradoxical injection rate effect; and the second establishes that the maximum paradoxical increase in peak drug level is by a factor of two. It is further shown that in order to approach this maximum paradoxical increase the impulse response must contain two isolated, sharp, narrow pulses of approximately equal area. Some examples of bimodal arterial dye-dilution curves from the literature are discussed as impulse responses; and there is also a discussion of the behavior of drug level maxima and minima at different injection rates.