PRINCIPLES OF TOXICOLOGY - Biology East Borneo

2.4 DISPOSITION: DISTRIBUTION AND ELIMINATION 47Figure 2.7 Plot of the logarithm of the concentration versus time for the linear one-compartment open model. C0is the concentration at time t = 0, assuming instantaneous distribution. (Reproduced with permission fromO’Flaherty, 1981, Figure 2.15a.)Calculated from the terminal slope of a plot of the natural logarithm of the concentration in thecentral compartment as a function of time, this half-life is designated the biological half-life. Itis the parameter most frequently used to characterize the in vivo kinetic behavior of an exogenouscompound.Other features of chemical kinetic behavior or of mode of administration may be incorporated intothe model as appropriate. For example, there may be more than one peripheral tissue compartment, asin Figure 2.1; or absorption, which is never truly instantaneous even for intravenous injection, may befirst-order instead. An oral exposure, in which the rate of absorption is usually considered to be directlyproportional to the amount remaining available in the GI tract, is an example of first-order uptake.The important group of models that incorporate non-first-order kinetics should also be mentioned.Absorption and distribution are conventionally considered to be passive, first-order processes unlessobservation dictates otherwise. However, elimination often is not first-order. Frequently this is becauseexcretion or metabolism is saturable, or capacity-limited, due to a limitation on the maximum numberof active transport sites in organs of excretion or the maximum number of active sites on metabolizingenzymes. When all active elimination sites are occupied, the elimination process is said to be saturated.Kinetically it is a zero-order process, operating at a constant maximum rate independent of the amountor concentration of the chemical in the body. At very low concentrations at which relatively fewelimination sites are occupied, capacity-limited kinetics reduces to pseudo-first-order kinetics. Capacity-limitedkinetics is often referred to as Michaelis–Menten kinetics, after the authors of an early paperanalyzing and interpreting this type of kinetic behavior. Classical kinetic models incorporatingMichaelis–Menten elimination have been developed.