Biology Reference
In-Depth Information
In determining PBPK parameters such as the apparent volume of distribution, the
data from an iv injection are one of the most important factors. As with oral dos-
ing, the volume of the vehicle is an important consideration. In general 1 to 2 ml/kg,
depending on whether it is an aqueous or a solvent vehicle, is appropriate. Although
the tail and hindpaw veins are adequate, the ideal administration is through the use
of a cannula inserted into the femoral or external jugular vein. Finally, several impor-
tant factors must be considered. First, in using a cannulated animal, care must be taken
that the affinity of the pesticide for the cannula material is low, so that adsorption to
the cannula material does not affect the results. Second, when these data go into a
PBPK model, the assumption is that the time of injection is t 0 . However, too rapid
an administration can result in acute toxicity to the animal, and thus a slower injec-
tion may be required. Provided that the total time of injection does not exceed 5% of
the half-life of the most rapid phase of the plasma concentration-time curve, it can be
regarded as an instantaneous dose ( Hayes, 2008 ). Finally, care must be taken that none
of the administered dose ends up in perivascular compartments. In addition to bolus
dosing, one can also carry out studies using iv infusion. The development of implant-
able osmotic mini-pumps has allowed the use of longer term pharmacokinetic studies
( Sai et al., 2009 ).
In many ways, the advances in PBPK models were made possible by an electri-
cal engineer working at Texas Instruments in the 1950s. In 1959 Jack Kilby filed a
patent application for the integrated circuit, and without the integrated circuit there
would not be ubiquitous and powerful computers, and without increasingly powerful
computers, the process of PBPK modeling would be prohibitively complex. There are
free, Web-based tools that can be used to build pharmacokinetic models, such as GNU
MCSim and PBPK.org. In addition there are many models that are available commer-
cially, including AcslIX, Cloe PK, and PK Sim. Again, the reader is referred to Chapter
6 of this text for a more complete discussion of the process.
CELL CULTURE, SUBCELLULAR FRACTIONS, AND RECOMBINANT
ENZYMES
Cell culturing techniques have facilitated great strides in toxicology research. The two
main limitations of these techniques are the changes that occur during isolation and
propagation in culture, and the difficulty of duplicating kinetic aspects of toxicant
exposure that occurs in the intact animal ( Hodgson, 2010 ).
One method of avoiding the issue of the loss of complexity with a cellular mono-
culture is the use of tissue slices. These are ≈200-µm slices that are prepared using
vibrating, precision-slicing instruments; however, their viability is limited to short-term
studies.
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