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Summary - Metabolism and Toxicology (WBFA016-05)
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METABOLISM AND TOXICOLOGYLECTURE 1: INTRODUCTION – De Graaf
Part I: Introduction
Metabolism is the chemical transformations that compounds undergo in the body (what does the
body do to a compound)
Toxicology is the name for adverse effects of chemical on organisms (what does the compound to the
body).
To enter cells compounds need to pass membranes and need to be lipophilic. Water-soluble
compound is inefficiently absorbed and easily excreted. Lipophilic compounds are efficiently
absorbed, they bind to proteins in the blood and clearance is therefore slow. However, to become
excreted, compounds need to be water-soluble. This change is executed by metabolism, in which the
drug becomes water-soluble in the liver, so it can be excreted.
Drug in the body will undergo the same process: Absorption – Distribution – Metabolism – Excretion.
Metabolism is the cause of paracetamol toxification. It is a lipophilic compound, so it needs to be
metabolized to be excreted by the body. It can be easily metabolized because it has an alcohol-group.
It can be sulphated and excreted via the urine. However, when it is hydroxylated at the nitrogen-atom
and dehydrated on the alcohol-site, the molecule NAPQI is created, which is toxic for the body.
Sometimes metabolites are more toxic than parent compound, this is called toxification or
bioactivation. Sometimes metabolites are less toxic than parent compound, this is called
detoxification.
Part II: Target interaction
Every drug has desirable effects, but also has undesirable effects (toxic / adverse effects). Toxic effects
may sometimes be desirable effect for other diseases (off label use). Adverse effects are described as
any (unwanted) effect of a drug that interferes with the normal function and adaptability of the body
to (stimuli from) the environment.
Targets of toxicity: receptors, proteins (enzymes, transporters, etc.), membrane-lipids, DNA/RNA, Ca2+
homeostasis, ion channels, mitochondria (energy). Toxic effects can have different manifestations:
Local vs. Systemic
Rapid onset / Acute vs. Delayed / Chronic
Reversible vs. Irreversible
Gradual vs. All-or-nothing
Direct vs. Indirect
Adverse effects are cell death, pharmacological/physiological effects, genotoxicity, carcinogenicity,
reproduction damage, teratogenicity, neurotoxicity, immunotoxicity, irritation.
Immunotoxicity: toxic effects by the immune system; immunological response to damage somewhere
in the body (e.g. sensitization, hapten formation), or toxic
effects on the immune system itself; toxic effect on B- or T-
lymphocytes.
On-target toxicity: undesirable effect due to exaggerated
pharmacological effect. For example, by increased exposure
of the target (higher blood concentrations, etc.), interaction
with the same target on/in another cell/organ.
,Off-target toxicity: undesirable effect via a completely different mechanism (different target) than
pharmacological effect. Dose response curve of the toxic effect ≠ intended pharmacological effect.
Part III: Toxicity and dose
“All substances are poisons; it is the dose that makes the poison.” – Paracelsus (ca. 1500 AD)
Dose-response curve shows a normal range in which there is a variation in the range of controls and a
range for responders, which lie above the normal range. This range is the same in the dose-effect
curve. Dose-response curve usually have a typical S-shape. Another type of graph is the U-shaped
dose-response curve, these have a region of homeostasis.
“All substances are poisons; it is the exposure that makes the poison.” – Paracelsus freely interpreted
Toxic effect depends on concentration at target and is related to the dose, but:
- There are differences in exposure routers
- Species/interindividual differences in ADME
- Saturation of effect, repair of detoxification
- Accumulation
- Time (dose x time)
- Interactions (induction, inhibition)
Toxicity is determined by
1. Characteristics of the compound
The compound potentially has an adverse effect. The structure, however, does not always
predict activity. There are some (chemical)class specific effects, but most compounds have a
unique toxicity profile. Also biological effects play a role, like receptor binding, affinity for
active center of an enzyme, DNA binding, etc.
2. Amount/dose/concentration
Degree of exposure to the hazard, so the amount administered and the bioavailability of the
drug. This is influenced by the administration route, metabolic activity, transporters in cell
membrane, blood flow, and time.
Part IV: Risk assessment
LD50, TC50, or EC50 are measures that reflect the potential of a compound to be toxic and/or
pharmaceutically active. Different compounds can be compared using these measures. The TD50 is
the dose of a drug necessary to provoke 50% of the maximal toxic effect. The TC50 is the
(plasma)concentration of a drug necessary to provoke 50% of the toxic effect. The ED50 and EC50 are
respectively the dose of a drug and the (plasma)concentration of a drug necessary to achieve 50% of
the desired effect.
LOAEL is the lowest observed adverse effect level. It is the
first tested dose/concentration of a drug that gives a
significant toxic effect (if a series of ascending doses /
concentrations is tested)
NOAEL shows no observed adverse effect levels. In a tested
series of ascending doses/concentrations, that
dose/concentration that is just lower than the LOAEL.
Hazard is anything that can cause harm. Risk is how great the chance that someone will be harmed by
the hazard.
, NOAEL mg bw
ADI or TDI or Rfd = given in [ ]
Safety factor kg day
The ADI is the acceptable daily intake.
Measures that reflect safety of drugs are the therapeutic index
= TD50/ED50 and the margin of safety (MOS) = TD1 / ED99.
Nowadays, it is not the toxic dose, but the toxic blood
concentration (animal) and the therapeutic blood
concentration (patient). So the formula is changed to TC1/EC99.
CBG-EMA-FDA: Balance between desirable and undesirable
effects. The risk-benefit ratio is investigated. Toxicology and
pharmacokinetics research is present in almost the whole process of drug research and development.
The toxicity is measured (1) in vitro, (2) laboratory animals, (3) healthy people, and (4) patients. In the
research phase toxicology and metabolism are screened. In the development phase toxicity and safety
pharmacology is investigated, as well as the ADME process of the drug. In the clinical phase the
carcinogenicity and teratogenicity is tested in laboratory animals, human pharmacokinetics and
toxicity and safety is investigated. Post-marketing the side effects are noted, and the
pharmacovigilance process is performed (detection, evaluation, and prevention of undesirable side
effects and interactions.).
The Lareb is the central collection point for all side effects of pharmaceutical drugs in the Netherlands.
Side effects are reported by patients and doctors. REACH stands for the Registration, Evaluation and
Authorization of Chemical substances and it is a law that ensures chemical (drug) testing.
LECTURE 2: TOXICOKINETICS – OLINGA
Part I: ABSORPTION
Chemical safety is based on the toxic properties of a compound
(what is the effect?) and exposure to the compound and its
metabolites (at which concentration in the sensitive organ?).
ADME is an important factor for toxicity, as it determines the
exposure to the final toxic compound. If a toxic compound is
disposed in the body, it can go to a variety of organ and can be
excreted differently. There are different types of toxicity:
- Local toxicity: compounds that are harmful without
being absorbed
- Systemic toxicity: compound harmful after absorption
and uptake into the general circulation
The bioavailability is the fraction of the
dose that reaches systemic circulation. A
drug can enter the systemic circulation via
the GI tract, skin, lung, and parenteral via
absorption.
- Oral administration: Epithelial cells
of intestinal wall
- Rectal administration: Epithelial
cells of the rectum
- Dermal administration: Epithelial
skin cells
- Pulmonary administration: Airway epithelial cells
, The transport through the membrane can occur in different ways, namely simple diffusion, channel-
mediated diffusion, carrier-mediated diffusion, or active transport.
Gastrointestinal tract properties affect intestinal uptake, because it has a very large surface (small
intestine = 250 m2). The absorption depends on pH, blood flow, metabolism in intestinal epithelium,
transporters in intestinal epithelium, nutritional status, and intestinal contractions. Also, bacteria are
involved in the processes of ADME (metabolism, bioactivation, detoxification).
Compound properties affect intestinal uptake. It depends on lipophilicity, pKa, affinity for uptake
carriers (Co2+ by Fe2+-carrier, and Pb2+ by Ca2+-carrier), size, solubility, affinity for metabolic enzymes,
and affinity for excretion carriers (like P-gp).
Factors which influence the intestinal toxicity is
mainly exposure:
- High concentration in the intestinal
lumen after oral administration:
concentration is dependent on volume
and intestine content.
- Degree of uptake in intestinal
epithelium (transporters)
- Degree of excretion from intestinal epithelium (transporters)
- Metabolism by intestinal bacteria, through intestinal wall
epithelial cell and/or pH
The first pass effect is determined by uptake and metabolism in the
intestine and liver.
The skin has a lot of different cell types and there are multiple ways
for a compound to enter the body via the skin. Absorption via the skin is a preferable way as it has a
large surface and it is little permeable. The absorption depends on skin
thickness, skin damage, hydratation, temperature, metabolism in the skin,
and solvent. Compound that are well absorbed by the skin are:
- Lipophilic compounds: CCl4, parathion
- Small hydrophilic compounds: hydrazine (NH2-NH2), nicotine, and
alcohol
Skin toxicity can occur after absorption through the skin: toxicity on the
skin itself, systemic toxicity, photosensitization, metabolism in the skin,
and/or allergy. However, it can also occur after systemic / oral
administration: skin toxicity through
photosensitization, and allergies.
VX is part of a family of nerve agents
used as a pesticide. Those are
organophosphorus ester chemical
warfare nerve gases, which are more
absorbed in the face area and less on
the hands. The mechanism is presented on the right. It leads to muscle contractions
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