Toxicokinetic Models

Unit 5

Federico Sinche
fsinche@yachaytech.edu.ec
Objectives:
• Learn the principles behind the classic
toxicokinetics
• Understand the compartmental models and
their applications in toxicology
• Recognize the roles of the toxicokinetic
parameters in the compartmental models
Outline
• Classic toxicokinetics
• One-compartment model
• Two-compartment model
• Application of two-compartment model
• Parameter models
 Classic Toxicokinetics
• Toxicokinetics
• The concentration of a compound in blood or plasma is in EQUIL with
the concentrations in tissues
• Changes in plasma toxicant concentrations should reflect changes in
tissue toxicant concentrations
• Compartmental pharmacokinetic models
• Central compartment (plasma)
• Central compartment (plasma) + peripherical compartments (tissues)
• Little information on tissue physiology or anatomical structure
• Can be used to predict the plasma chemical concentrations at different doses
(effective dose and dose regimens in toxicity studies)

Ref.: Casarett & Doull’s 2015

 One-Compartment Model
• The 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

One-Compartmental pharmacokinetic model

ka is the first-order extravascular absorption rate constant into the central compartment
(1), kel is the first-order elimination rate constant rom the central compartment (1)
Ref.: Casarett & Doull’s 2015
 Toxicant conc
One-Compartment Model Cont’d

Plasma concentration versus time curves of toxicants exhibiting kinetic behavior conforming to a one-compartment
model following intravenous bolus injection.
Elimination rate constant (kel) from the slope between the log-linear conc and time curve

Ref.: Casarett & Doull’s 2015

 One-Compartment Model Cont’d
• Linear relationship
• A straight line from plotting the logarithm of plasma concentrations
versus time, the kinetics of the xenobiotic can be described with a one-
compartment model
• Assumptions:
• Toxicokinetics that rapidly equilibrate or mix uniformly between blood and the
various tissues relative to the rate of elimination
• The body depicted as a homogenous unit
• The changes that occur in the plasma concentration reflect proportional
changes in tissue chemical concentrations

where C is the blood or plasma chemical concentration over time (t)

C0 the initial blood concentration at time (t=0)
kel the first-order elimination rate constant with dimensions of reciprocal time (t -1). It represents
the overall elimination of the chemical (biotransformation, exhalation and/or excretion pathways

Ref.: Casarett & Doull’s 2015

 One-Compartment Model Cont’d

Ref.: Casarett & Doull’s 2015

 Two-Compartment Model
• The Two-Compartment Model
• Non-straight line because there is more than one dispositional phase
• The chemical requires a longer time for tissue concentrations to reach
equilibrium with the concentration in plasma (multicompartmental
analysis)

Ref.: Casarett & Doull’s 2015

Two-Compartmental pharmacokinetic model

ka is the first-order extravascular absorption rate constant into the central compartment (1), kel is the first-order elimination
rate constant rom the central compartment (1)
kl2 and k2l are the first-order rate constants for distribution of chemicals into and out of the peripheral compartment (2)
kl0 is the first-order elimination rate constant from the central compartment
 Two-Compartment Model Cont’d
• Exponential relationship
• The distribution and elimination of the xenobiotic from the plasma
• Two monoexponential terms (two compartments)
• Assumptions:
• More than one dispositional phase
• Longer time for tissue concentrations to reach EQUIL
• The distribution phase may last for only a few minutes or for hours or days

where C is the blood or plasma chemical concentration over time (t)

A and B are proportionality constants (coefficients in units of toxicant concentration)
α and β are the first-order distribution and elimination rate constants, respectively
During the distribution (α) phase, concentrations of the chemical in the plasma decrease more rapidly than
they do in the post-distributional elimination (β) phase

Ref.: Casarett & Doull’s 2015

 Toxicant conc
Two-Compartment Model Cont’d

Plasma concentration versus time curves of toxicants exhibiting kinetic behavior conforming to a two-compartment
model following intravenous bolus injection.
Typical tissues associated with the central (1) and peripheral (2) compartments
α and β are the first-order distribution and elimination rate constants, respectively

Ref.: Casarett & Doull’s 2015

 Two-Compartment Model Cont’d

Ref.: Casarett & Doull’s 2015

 Two-Compartment Model Cont’d

Ref.: Casarett & Doull’s 2015

 Application of Two-Compartment
Model
• Gentamicin
• Garamycin© is an antibiotic used to treat several types of bacterial
infections (e.g., pneumonia)
• Aminoglycosides → excreted unchanged in the urine
• Complete recovery of the dose can be
achieved only if urine is collected for
periods as long as 10 to 20 d
• Case study
• Patients ill with pneumonia
• Patients treated with antibiotic
• Millard Filmore Hospital
• Monitoring during and after therapy

Ref.: https://phytotechlab.com/gentamicin-sulfate.html
 Application of Two-Compartment
Model Cont’d

Ref.: https://www.youtube.com/watch?v=3hTsve9jjsQ
 Application of Two-Compartment
Model Cont’d

Ref.: https://www.youtube.com/watch?v=pQdtmLSCZi0
 Application of Two-Compartment
Model Cont’d

Ref.: Schentag & Jusko, 1977

 Application of Two-Compartment
Model Cont’d

Excretion

Serum

Ref.: Schentag & Jusko, 1977

 Application of Two-Compartment
Model Cont’d

Ref.: Schentag & Jusko, 1977

 Parameter Models
• Elimination
• Include biotransformation, exhalation and excretion
• Mostly a first-order process: the rate of elimination at any times 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
• Logarithmic equation: y = mx + b

where logC is the y-intercept (initial concentration)

kel /2.3030 is the slope of the line (min-1)

C/C0 is the fraction of dose remaining in the body over time (t)

Ref.: Casarett & Doull’s 2015

 Parameter Models Cont’d
• Apparent Volume of Distribution
• The Vd is the apparent space into which an amount of chemical is
distributed in the body to result in a given plasma concentration
• A chemical will distribute out of plasma and into other body tissue
• The Vd is a proportionality constant that relates the total amount of
chemical in the body and tissues to its concentration in plasma (L/kg of
body wt)

One-compartment model Two-compartment model

where Doseiv is the intravenous dose where Doseiv is the intravenous dose at time zero
C0 is the concentration of chemical in plasma at time zero β is the elimination rate constant
AUC0∞ is the area under the chemical concentration

Ref.: Casarett & Doull’s 2015

 Parameter Models Cont’d
• Clearance
• The “Cl” is the rate of chemical elimination from the body in terms of
volume of fluid containing chemical that is cleared per unit of time
(mL/min)
• High clearance values indicate efficient and rapid removal
• Low clearance values indicate slow and less efficient removal

Others

Total body clearance is the sum of clearances by Each organ clearance is determined by blood perfusion
individual eliminating organs flow through the organ and the fraction of toxicant in the
arterial inflow that is irreversibly removed

Clearance for Clearance for

One-compartment model Two-compartment model
Ref.: Casarett & Doull’s 2015
 Parameter Models Cont’d
• Half-life of elimination
• The T1/2 is the time required for the blood or plasma chemical
concentration to decrease by one-half, and is dependent on both Vd and
Cl
• For compounds eliminated by first-order kinetics, the time required for
the plasma concentration to decrease by one-half is constant
• The half-life of a chemical obeying first-order elimination kinetics is
independent of the dose, and does not change with increasing dose, and
does not change with increasing dose

kel or β can be used for elimination rate constant

Ref.: Casarett & Doull’s 2015

 Parameter Models Cont’d
• Bioavailability
• The resulting index quantifies the fraction of dose absorbed systemically
and is called bioavailability (F)
• Intravenous administration, all of the chemical is delivered to the
systematic circulation (100% bioavailable)
• Factors altering the systemic availability
• Limited absorption after oral dosing
• Intestinal first-pass effect
• Hepatic first-pass effect
• Mode of formulation (e.g., dissolution rate)
• Complete availability of chemical to systemic circulation, F = 1
• F < 1, less than 100% of the dose reaches systemic circulation

where AUCpo is the area under the plasma concentration

Dosepo is the area under the plasma concentration
Ref.: Casarett & Doull’s 2015
 Parameter Models Cont’d
• Saturation Toxicokinetics
• Biotransformation, active transport processes, and protein binding have
finite capacities and can be saturated
• When the concentration of a chemical in the body is higher than the Km
(chemical conc at one-half Vmax, the maximum metabolic capacity)
• The transition from first-order to saturation kinetics → it can lead to
prolonged residency time of a compound in the body or increased
concentration at the target site of action

Ref.: Casarett & Doull’s 2015

 Take Home Messages
1. Classic toxicokinetics provide information on the
distribution of the drugs in the biological systems
2. The one-compartment model is the simplest
toxicokinetic analysis to determine xenobiotic
concentrations in plasma
3. The two-compartment model requires more EQUIL
time as the xenobiotic is being perfused into
peripherical tissues
4. Depiction of two-compartments can be observed in
drugs that are readily excreted and do not undergo
compound transformation
 References
Klaassen, C. D., & Amdur, M. O. (Eds.). (2013). Casarett and Doull's toxicology: the basic science of poisons (Vol. 1236, p.
189). New York: McGraw-Hill.

Schwarzenbach, R.P., Gschwend, P. M., Imboden, D. M. Environmental Organic Chemistry. 2nd Edition. (2003). John Wiley &
Sons, Inc. Hoboken, New Jersey. Pgs 1327.

Stolerman, I. (Ed.). (2010). Encyclopedia of psychopharmacology. 2nd Edition. Springer Science & Business Media. ISBN 978-
3-642-3671-5

Schentag, J. J., & Jusko, W. J. (1977). Renal clearance and tissue accumulation of gentamicin. Clinical Pharmacology &
Therapeutics, 22(3), 364-370.

https://phytotechlab.com/gentamicin-sulfate.html

https://www.youtube.com/watch?v=pQdtmLSCZi0

https://www.youtube.com/watch?v=3hTsve9jjsQ