Page 169 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

136 SECTION | I General

VetBooks.ir Measures of Absorption Half-Life
A compound’s half-life in plasma (T 1 /2 ) is a composite
Often, only a fraction of the total dose to which an
animal or human is exposed gets absorbed systemically.
ability to eliminate the compound (CL), as well as the
This fraction is referred to as the bioavailability (F) parameter that is dependent on both the body’s inherent
and is calculated by comparing the areas under the plasma extent to which the compound is distributed through the
time concentration curves for the toxic compound admin- body (V D ). This relationship is illustrated in the following
istered intravenously versus the typical route of exposure. equation:
These data are not readily available for most toxic com-
0:693 3 V D
pounds, although the relative bioavailability from different T1 5
/2 CL
routes (e.g., oral vs dermal) is often known. Other measures
of the rate and extent of absorption include the absorption Widely distributed compounds have long half-lives
rate constant (k a ), maximum measured concentration in the due to their low concentrations in plasma (assuming first-
plasma (C max ) and time after exposure when this concentra- order kinetics, where the rate of elimination is propor-
tion is measured (T max ). tional to the amount of drug presented to the eliminating
organ). Similarly, compounds with low CL values have
long half-lives too.
Volume of Distribution
The total volume of fluid in which a toxic substance must Flip-Flop Kinetics
be dissolved to account for the measured plasma concen-
Flip-flop kinetics refers to a situation when the rate of
trations is known as the apparent volume of distribution
absorption of a compound is significantly slower than its
(V D ). If a compound is distributed only in the plasma
rate of elimination from the body. The compound’s per-
fluid, the V D is small and plasma concentrations are high.
sistence in the body therefore becomes dependent on
Conversely, if a compound is distributed to all sites in the
absorptive rather than elimination processes (Fig. 8.3).
body, or if it accumulates in a specific tissue such as fat
This sometimes occurs when the route of exposure is
or bone, the V D becomes large and plasma concentrations
dermal.
are low. The value of this parameter is calculated from
the multiexponential equation that is fit to the data using:
Dose Residues
V D 5 P n
i51 C i An additional concern with food-producing animals is the
potential for adverse effects in the human consumer if
Calculation of apparent volume of distribution from tra-
edible tissues harvested from exposed animals contain
ditional pharmacokinetic parameters where C i refers to the
harmful residues of toxic compounds. Tolerances (also
intercepts of the various phases of the curve with the y-axis.
known as maximum residue levels in countries other than
Clearance
60
Total body clearance (CL) is the pharmacokinetic param-
50
eter that reflects the body’s inherent ability to eliminate a
xenobiotic through organs of elimination. The value of 40
this parameter represents the volume of blood cleared of Rapid absorption
the toxic substance per unit time. If the total absorbed Concentration 30 Slow absorption
dose is known, CL can be calculated. Many times the 20
absorbed dose in not known, in which the calculated
value of this parameter reflects not only CL but also an 10
unknown value for bioavailability (F). The lower F is, the
higher the calculated value for a specific dose will be: 0
0 10 20 30 40
Dose
CL 5 Time
AUC 02N
FIGURE 8.3 Plasma concentrations comparing a slow rate of absorp-
Equation used to calculate total body clearance, where tion to a rapid rate of absorption, demonstrating “flip-flop” kinetics,
AUC 0 N is the area under the plasma time concentration where persistence of the compound is dependent on the rate of absorp-
curve extrapolated to infinity. tion, rather than the rate of elimination.