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TIME-DEPENDENT PHARMACOKINETICS
1. INTRODUCTION
The literature in pharmacokinetics indicates that for a number of years, the term
nonlinearity has been associated almost exclusively with dose-dependent changes in
pharmacokinetic parameters. The other type of nonlinearity, time dependency, has only
been rarely alluded to and then, mostly in the context of chronobiology. No systematic
treatment of time-dependent kinetics has appeared to date. Considering that any treatment
of drug accumulation in the simplest pharmacokinetic model must assume that all
pharmacokinetic parameters are time-invariant. However, it should not be concluded
that the paucity of information on this subject reflects an awareness of the implications of
the assumption of time-invariance. Rather, it is probably related to the fact that studies
of time dependency necessarily involve longitudinal observations beyond those of typical
single dose pharmacokinetic studies. This review represents an attempt to classify and
analyze the various types of time dependencies based on the available literature.
2. CLASSIFICATION
A major distinguishing feature between dose and time dependency is that the latter
involves an actual physiological or biochemical change in the organ(s) of the body
associated with the drug disposition parameters in question. For example, in time dependence
of the auto or heteroinduction type, the increase in drug intrinsic clearance results
from an increase in amount of enzyme (in protein synthesis). However, in a typical
Michaelis-Menten dose dependency, drug clearance changes with concentration and
such a system should not be considered time-dependent simply because the values of
pharmacokinetic parameters also change with time. If that system was truly time-dependent,
drug clearance should change with time while drug concentration is invariant (i.e.,
at steady state). However, the possibility exists, as will be shown later, that dose and time
dependency can coexist simultaneously.
There are at least two types of time dependencies. The first one is related to the fact
that rhythms are a fundamental property of most physiologic functions. The word chronopharmacokinetics*
has been used to describe these phenomena when these rhythms
manifest-themselves in a corresponding change in the pharmacokinetic parameter of a
drug. Typical examples include circadian rhythms in drug absorption, distribution and
elimination. The second type of time dependency is best exemplified by the phenomena
of auto or heteroinduction and could be classified as chemically-induced. It starts only
after the introduction of an exogenous substance in the body and ultimately disappears
after the causing agent is removed. However, the above distinguishing features are not
absolute since certain rhythms are also dependent on environmental conditions and can
therefore be manipulated exogenously. Also, it is conceivable that rhythmic changes in
kinetic parameters could be chemically induced or altered. Time-dependent changes in
pharmacokinetic parameters cannot always be classified within one of these two categories.
A perusal of the literature shows the existence of a number of irregularities