Page 144 - The Toxicology of Fishes

124 The Toxicology of Fishes

100

80

% AChE INHIBITION IN BRAIN 60

40

20

0
0 20 40 60 80 100 120 140
HOURS
FIGURE 3.30 Metabolism of paraoxon by carboxylesterase (CaE). Paraoxon concentrations were linked to acetylcho-
linesterase (AChE) inhibition in the brain of rainbow trout using a physiologically based toxicokinetic/toxicodynamic model.
Model predictions with and without CaE metabolism are shown as solid and dashed lines, respectively; individual points
show measured levels of AChE inhibition. (Adapted from Abbas, R. and Hayton, W.L., Toxicol. Appl. Pharmacol., 145,
192–201, 1997.)

Noncompartmental Analysis
Noncompartmental analysis can be used to estimate of the volume of distribution (V ), total body
ss
clearance (CL), and persistence of a chemical (mean residence time). Because it does not rely on curve-
fitting techniques to fit model-based equations to experimental data, this approach avoids a number of
statistical considerations such as choice of weighting function, multiple minima in the sum of squares
fitting criterion, and large variance in parameter values. Although this approach does not characterize
the kinetics of distribution of chemical, as do compartmental and PBTK modeling methods, it can be
used to estimate basic pharmacokinetic parameters, even when the data are highly variable. Noncom-
partmental analysis was used by Barron et al. (1987b) to investigate the temperature dependence of
di-2-ethylhexylphthalate kinetics in rainbow trout. Total body clearance values calculated in this manner
were very close to those estimated using a compartmental model. Alavi et al. (1993) used noncompart-
mental analysis to estimate pharmacokinetic parameters for sulfachlorpyridazine in channel catfish. To
date, however, very few researchers have used noncompartmental methods in kinetic studies with fish.
The application of noncompartmental analysis to bolus dosing data is described below. Modifications
of this approach are required to deal with more complex dosing regimens.

Intravascular Bolus Administration
No explicit model structure is used in noncompartmental analysis; however, the chemical must be
measured in and exit the body from the pool or compartment of its introduction (Matis et al., 1985).
The method is based on the concept of mean residence time (MRT) of the chemical in the body. The
MRT is the average time that all the molecules of chemical spend in the body after their simultaneous
administration; for example, if the dose consisted of 100 chemical molecules administered as a bolus,
then the MRT would be the sum of the individual residence times of each chemical molecule divided
by 100. Following bolus administration, the rate of chemical elimination at any time is: