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 Absorption, Distribution,
and Excretion
Michael A. Trush, PhD
Bloomberg School of Public Health
 Section A

The Toxicological Process

 Definition

Š Toxicology is the study of poisons

Š Poisons are chemical/physical agents that
produce adverse responses in biological
organisms

4
“What is there that
is not poison? All
things are poison
and nothing without
poison. Solely, the
dose determines
that a thing is not
a poison”
Paracelsus (1493-1541)

5
The Toxicological Paradigm

6
 Toxicokinetics
Š Toxicokinetics is the quantitation of the time course of
toxicants in the body during the processes of
absorption, distribution, biotransformation, and
excretion or clearance of toxicants. In other words,
toxicokinetics is a reflection of how the body handles
toxicants as indicated by the plasma concentration of
that xenobiotic at various time points
Š The end result of these toxicokinetic processes is a
biologically effective dose of the toxicant.

7
 Toxicodynamics
Š Toxicodynamics refers to the molecular, biochemical, and
physiological effects of toxicants or their metabolites in
biological systems
Š These effects are result of the interaction of the
biologically effective dose of the ultimate (active) form of
the toxicant with a molecular target

8
 Molecular Targets Concept
Š The toxic action of a chemical is a consequence of the
physical/chemical interaction of the active form of that
chemical with a molecular target within the living
organism

Continued 9
Molecular Targets Concept

10
 Examples of Molecular Targets
Š Proteins
– Arylhydrocarbon(Ah) receptor—Dioxin
– Hemoglobin—CO
Š Lipids—Carbon tetrachloride
Š DNA—Aflatoxin

11
 Dose-Response Concept
Š The magnitude of the toxic effect will be a function of the
concentration of altered molecular targets, which in turn
is related to the concentration of the active form of the
toxicant( biologically effective dose) at the site where the
molecular targets are located.

12
The Toxicological Process

13
The Toxicological Process

14
 Section B

Transport Process Mechanisms

 Membrane Transport
of Xenobiotics

Š The absorption, distribution, and excretion of xenobiotics

involves passing through various cell and organ
membranes.
Š This occurs through various transport mechanisms

16
Membrane Transport
of Xenobiotics

17
 Xenobiotics:
Transport Mechanisms
Š Factors affecting membrane transport of chemicals:
– Molecular weight/shape
– Charge
– Lipid solubility
– Membrane composition
– Membrane thickness

18
 Types of Transport
Š Simple diffusion
Š Facilitated diffusion
Š Active transport
Š Pinocytosis/receptor-mediated uptake
Š Filtration

19
Types of Transport

20
 Characteristics of
Simple Diffusion
Š Transport proceeds in the direction of the electrochemical
potential (concentration) gradient
Š Transport is not saturable at high concentration gradients
Š No structural specificity
Š No energy requirement
Š Inherently symmetrical transport

21
 BOTH PASSIVE MEDIATED and
ACTIVE MEDIATED TRANSPORT
INVOLVE the USE of CARRIER
PROTEINS

22
Carrier-Mediated Transport

23
 Characteristics of
Passive Mediated Transport
Š Transport proceeds in the direction of the electrochemical
potential (concentration) gradient
Š The process is saturable at high concentration gradients,
i.e., there is a maximum rate of transport

Continued 24
 Characteristics of
Passive Mediated Transport
Š Structural specificity (specific inhibitors)
Š No energy requirements
Š Inherently symmetrical transport

25
 Characteristics of
Active Mediated Transport
Š Transport can proceed against an electrochemical
potential (concentration) gradient
Š The process is saturable at high concentration gradients
Š Structural specificity
Š Requires cellular energy
Š Asymmetrical transport

26
 Active Mediated Transport

Š The structure of the herbicide paraquat (A) and the

polyamines putrescine (B) and spermine (C)

27
 Pinocytosis/Phagocytosis/
Receptor Mediated Endocytosis
PHA
GO
cell membrane CYT
OSI
S

SIS
Pinocytosis channel
T O pseudopods
C Y
O
PIN

Pinocytic vessels
28
 Filtration

Š Transport of solutes as a consequence of

bulk flow of fluid (aqueous) phase
Š Glomerulus of kidney is a good example of
site where filtration occurs

29
 Section C

Toxicokinetics
 Systemic Kinetics: Outline
Š Physiological basis of toxicokinetics
Š Biliary excretion route for foreign compounds
Š Barriers
Š Major difference between a general (non-neural) and
brain capillary
Š Excretion pathways

31
32
 Biliary Excretion Route For Foreign
Compounds

Image source: NIH/NIDDK. Public Domain. 33

 Systemic Kinetics: Barriers

Š Blood-brain barrier
Š Placenta
Š Blood-testicular barrier

34
Major Difference between a General
(Non-Neural) and a Brain Capillary

35
 Excretion Pathways

Š Respiratory excretion
– Mucocilliary clearance
Š Gastrointestinal excretion
– Biliary excretion
– Entero-hepatic circulation
Š Urinary excretion
– Glomerular filtration
– Trans-tubular secretion
36
 Renal Excretion of Chemicals
Afferent arteriole

Glomerulus
Efferent arteriole

Bowman’s capsule Unfiltered drug

Passive
Filtered drug reabsorption
Active
secretion Water soluble
Proximal tubule
Lipid soluble

Excretion and/or further passive reabsorption

37
 Other Routes of Excretion

Š Milk
Š Sweat
Š Hair
Š Nails
Š Saliva

38
 Biological Half Life

Š The biological half-life (T1/2) is the time

required for some measure of the amount
of a chemical in the body (for example,
body burden, tissue concentration) to
decrease to 1/2 its value at the beginning
of the observational interval

Continued 39
 Section D

Toxicokinetics and PBK Modeling

 PBPK Modeling
Physiologically Based Pharmacokinetic (Toxicokinetic)

Š Purpose
– To mathematically model how a
substance is absorbed, distributed, and
metabolized in the body to reduce
uncertainties in determining the
estimated dose

41
 PBPK Modeling

Source: Casarett & Doull, Chaps. 5 and 7, 1996 Continued 42

Tox, lec 1, slide 6
 PBPK Modeling
Blood Styrene Levels: Rat vs. Human

44
Vinyl Chloride Metabolism
O
C H
H
C
Cl
H
Chloroacetaldehyde
P450

GSH conjugation

Covalent binding to proteins

45
 Vinyl Chloride – Exposure, Metabolism in Rats
& the Incidence of Hepatic Angiosarcoma

Exposure μg of VC per L of air μg of VC metabolized/4 hr Incidence %

50 128 739 2
250 640 2435 7
500 1,280 3413 12
2,500 6,400 5030 22
6,000 15,360 5003 22
10,000 25,600 5521 15

Data source: Gehring et al. Toxicol Appl Pharmacol. 1978;44:581-591 46