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 Log Out
CHAPTER 7
TOXICOKINETICS
Michele A. Medinsky and John L. Valentine
INTRODUCTION
CLASSIC TOXICOKINETICS
One-Compartment Model
Two-Compartment Model
Elimination
Apparent Volume of Distribution
Clearance
Half-Life
Saturation Toxicokinetics
Bioavailability
Computer Software
PHYSIOLOGIC TOXICOKINETICS
Basic Model Structure
INTRODUCTION
The study of the kinetics of chemicals was originally initiated for
drugs and consequently was termed pharmacokinetics. However,
toxicology is not limited to the study of adverse drug effects but
entails an investigation of the deleterious effects of all chemicals.
Therefore, the study of the kinetics of xenobiotics is more prop-
erly called toxicokinetics. Toxicokinetics refers to the modeling and
mathematical description of the time course of disposition (ab-
sorption, distribution, biotransformation, and excretion) of xeno-
biotics in the whole organism. The classic way to describe the ki-
netics of drugs is to represent the body as consisting of one or two
compartments even if those compartments have no apparent phys-
iologic or anatomic reality. An alternate approach, physiologically
based toxicokinetics, represents the body as a series of mass bal-
ance equations that describe each organ or tissue on the basis of
physiologic considerations. It should be emphasized that there is
no inherent contradiction between the classic and physiologically
based approaches. Classic pharmacokinetics, as will be shown, re-
quires certain assumptions that the physiologically based models
do not require. Under ideal conditions, physiologic models can pre-
dict tissue concentrations, whereas classic models cannot. How-
ever, the values of the appropriate parameters are often unknown
or inexact, hampering meaningful physiologically based toxicoki-
netic modeling.
CLASSIC TOXICOKINETICS
Often, it is difficult to obtain relevant biological tissues in order to
ascertain a chemical or chemical concentration in the body and
then relate that chemical concentration to a toxicologic response.
The least invasive and simplest method to gather information on
absorption, distribution, metabolism, and elimination of a com-
pound is by sampling blood or plasma over time. If one assumes
that the concentration of a compound in blood or plasma is in equi-
225
226 UNIT 2 DISPOSITION OF TOXICANTS
Compartments
Parameters
Anatomic
Physiologic
Thermodynamic
Transport
Perfusion-Limited Compartments
Diffusion-Limited Compartments
Specialized Compartments
Lung
Liver
Blood
CONCLUSION
librium with concentrations in tissues, then changes in plasma
chemical concentrations reflect changes in tissue chemical con-
centrations, and relatively simple pharmacokinetic models can
adequately describe the behavior of that chemical in the body.
Compartmental pharmacokinetic models consist of a central
compartment representing plasma and tissues that rapidly equili-
brate with chemical, connected to one or more peripheral com-
partments that represent tissues that more slowly equilibrate with
chemical (Fig. 7-1). Chemical is administered into the central com-
partment and distributes between central and peripheral compart-
ments. Chemical elimination occurs from the central compartment,
which is assumed to contain rapidly perfused tissues capable of
eliminating chemical (e.g., kidneys and liver). Advantages of com-
partmental pharmacokinetic models are that they require no infor-
mation on tissue physiology or anatomic structure. These models
are valuable in predicting the plasma chemical concentrations at
different doses, in establishing the time course of chemical in
plasma and tissues and the extent of chemical accumulation with
multiple doses, and in determining effective dose and dose regi-
mens in toxicity studies (Gibaldi and Perrier, 1982).
One-Compartment Model
The simplest toxicokinetic analysis entails measurement of the
plasma concentrations of a xenobiotic at several time points after
the administration of a bolus intravenous injection. If the data ob-
tained yield a straight line when they are plotted as the logarithms
of plasma concentrations versus time, the kinetics of the xenobi-
otic can be described with a one-compartment model (Fig. 7-2).
Compounds whose toxicokinetics can be described with a one-
compartment model rapidly equilibrate, or mix uniformly, between
blood and the various tissues relative to the rate of elimination. The
one-compartment model depicts the body as a homogeneous unit.
This does not mean that the concentration of a compound is the
same throughout the body, but it does assume that the changes that
Generally, a curve of this type can be resolved into two
monoexponential terms (a two-compartment model) and is de-
scribed by
C  A  e    t    e   t

Figure 7-1. Compartmental pharmacokinetic models where ka is the first-
order extravascular absorption rate constant into the central compart-
ment (1), kel is the first-order elimination rate constant from the central
compartment (1), and k12 and k21 are the first-order rate constants for
distribution of chemical into and out of the peripheral compartment (2)
in a two-compartment model.
occur in the plasma concentration reflect proportional changes in
tissue chemical concentrations (Rowland and Tozer, 1980).
In the simplest case, a curve of this type can be described by
the expression
C  C0  ekelt
where C is the blood or plasma chemical concentration over time
t, C0 is the initial blood concentration at time t  0, and kel is the
first-order elimination rate constant with dimensions of reciprocal
time (e.g., t1).
Two-Compartment Model
After the rapid intravenous administration of some chemicals, the
semilogarithmic plot of plasma concentration versus time does not
yield a straight line but a curve that implies more than one dispo-
sitional phase. In these instances, the chemical requires a longer
time for its concentration in tissues to reach equilibrium with the
concentration in plasma, and a multicompartmental analysis of the
results is necessary (Fig. 7-2). A multiexponential mathematical
equation then best characterizes the elimination of the xenobiotic
from the plasma.
CHAPTER 7 TOXICOKINETICS
where A and B are proportionality constants and  and  are the
first-order distribution and elimination rate constants, respectively
(Fig. 7-2). During the distribution () phase, concentrations of the
chemical in the plasma decrease more rapidly than they do in the
postdistributional elimination () phase. The distribution phase
may last for only a few minutes or for hours or days. Whether the
distribution phase becomes apparent depends on the time when the
first plasma samples are obtained, and on the relative difference in
the rates of distribution and elimination. If the rate of distribution
is considerably rapid relative to elimination, the timing of blood
sampling becomes critical in the ability to distinguish a distribu-
tion phase. The equivalent of kel in a one-compartment model is 
in a two-compartment model.
Occasionally, the plasma concentration profile of many com-
pounds cannot be described satisfactorily by an equation with two
exponential terms—for example, if the chemical has an excep-
tionally slow distribution into and redistribution out of a deep pe-
ripheral compartment or tissue. Sometimes three or four exponen-
tial terms are needed to fit a curve to the plot of log C versus time.
Such compounds are viewed as displaying characteristics of three-
or four-compartment open models. The principles for dealing with
such models are the same as those used for the two-compartment
open model, but the mathematics are more complex and beyond
the scope of this discussion.
Elimination
Elimination includes biotransformation, exhalation, and excretion.
The elimination of a chemical from the body whose disposition is
described by a one-compartment model usually occurs through a
first-order process; that is, the rate of elimination at any time is
proportional to the amount of the chemical in the body at that time.
First-order reactions occur at chemical concentrations that are not
sufficiently high to saturate elimination processes.
The equation for a monoexponential model, C  C0 
ekelt, can be transformed to a logarithmic equation that has the
general form of a straight line, y  mx  b:
log C  (kel2.303)  t  log C0
where log C0 represents the y-intercept or initial concentration, and
(kel2.303) represents the slope of the line. The first-order elim-
ination rate constant (kel) can be determined from the slope of the
log C versus time plot (i.e., kel  2.303  slope). The first-order
elimination rate constants kel and  have units of reciprocal time
(e.g., min1 and h1) and are independent of dose.
Mathematically, the fraction of dose remaining in the body
over time (CC0) is calculated using the elimination rate constant
by rearranging the equation for the monoexponential function and
taking the antilog to yield
CC0  Anti log [(kel2.303)  t]
Thus, if the elimination rate constant is, for example, 0.3 h1,
the percentage of the dose remaining in the body (CC0  100)
and the percentage of the dose eliminated from the body after 1 h,
227
 Figure 7-2. Concentration versus time curves of chemicals exhibiting behavior of a one-compartment phar-
macokinetic model (top) and a two-compartment pharmacokinetic model (bottom) on a linear scale (left) and
a semilogarithmic scale (right).

Elimination rate constants, kel and  are determined from the slope of the log-linear concentration versus time
curve. Half-life (T12) is the time required for blood or plasma chemical concentration to decrease by one-half.
C0 is the concentration of the chemical at t  0 determined by extrapolating the log-linear concentration time
curve to the Y-axis (t  0).

i.e., 1  (CC0  100), are 74 and 26 percent, respectively, re-
gardless of the dose administered (Table 7-1). The percentage of
the total dose eliminated at one hour is said to be independent of
dose.
Apparent Volume of Distribution
In a one-compartment model, all chemical is assumed to distrib-
ute into plasma and tissues instantaneously. The apparent volume
of distribution (Vd) is a proportionality constant that relates the to-
Table 7-1
Elimination of Four Different Doses of a Chemical at 1 Hour
After Administration as Described by a One-Compartment
Open Model and First-Order Toxicokinetics with a kel of 0.3 h 1
tal amount of chemical in the body to the concentration of a xeno-
biotic in plasma, and is typically described in units of liters or liters
per kilogram of body weight (Kato et al., 1987). Vd is the appar-
ent space into which an amount of chemical is distributed in the
body to result in a given plasma concentration. For example, en-
vision the body as a tank containing an unknown volume (L) of
well mixed water. If a known amount (mg) of dye is placed into
the water, the volume of that water can be calculated indirectly by
determining the dye concentration (mg/L) that resulted after the
dye has equilibrated in the tank simply by dividing the amount of
dye added to the tank by the resultant concentration of the dye in
water. Synonymously, the apparent volume of distribution of a
chemical in the body is determined after intravenous bolus ad-
ministration, and is mathematically defined as the quotient of the
amount of chemical in the body and its plasma concentration. Vd


is calculated as
CHEMICAL CHEMICAL CHEMICAL

Vd  Doseiv(  AUC0

DOSE , REMAINING , ELIMINATED , ELIMINATED , )
mg mg mg % of dose

10 7.4 2.6 26 where Doseiv is the intravenous dose or known amount of chemi-
30 22 8 26 cal in body at time zero;  is the elimination rate constant; and

AUC0 is the area under the chemical concentration versus time
90 67 23 26
250 185 65 26 curve from time zero to infinity. The product,   AUC0 , is the


concentration of xenobiotic in plasma.

Toxicokinetics
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