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Metabolism and toxicology lecturesIntroduction
Metabolism is the chemical transformation that compounds
undergo in the body, so what does the body do to a compound.
Toxicology are the adverse effects of chemicals on organisms. What
does the compound do to the body. Many drugs are lipophilic
because when they are lipophilic they can easily pass membranes.
Water-soluble compounds are inefficiently absorbed and easily
excreted. Fat-soluble drugs are absorbed and bind to albumin, a
plasma protein. Lipophilic compounds are, because of this binding,
slowly cleared. To become excreted the compounds need to be
water-soluble, this process of transformation takes place in the
liver. ADME is the absorption, distribution, metabolism and
excretion and these processes determine the concentration of a
drug in the body. Toxicity is for a large part determined by
metabolites because sometimes metabolites are more toxic than
their parent compound is, this is called toxification. Metabolites can be less toxic than their parent
compound, this is called detoxification. Every drug has a desirable effect and an undesirable effect
which is the toxic effect, this effect may be desirable for other diseases or it can be an adverse drug
reaction (ADR). Adverse effect is any effect of a drug that interferes with the normal function and
adaptability of the body to the environment. On-target toxicity is toxicity that is induced due to
interaction with the pharmacological target. Off-target toxicity is toxicity that is induced due to a
different mechanism then the pharmacological target.
With an increase of the dose a drug may become toxic, all drugs are toxic when too much of them is
taken. Hormesis is a special form of a dose response curve, in this case a certain dose of vitamins or
something else is needed to prevent deficiency or toxicity. However, the exposure makes the drug
toxic and not the dose, the same dose does not always give the same exposure, this could be
because of administration routes, enzymes, accumulation, time and interactions. The compound
characteristic can also influence the toxicity, from one drug a low dose can be toxic whereas from the
other this might be a much higher dose. So the toxicity is determined by the characteristics of the
compounds and the dose and concentration the exposure is done.
Measures of toxicity are LD50 (lethality of a compound), TC50 (toxicity of a compound) and EC50
(effectivity of a compound), these are used to reflect on the potential of a compound to be toxic and
pharmaceutically effective. TD50 = the dose that is necessary to provoke 50% of the maximal toxic
effect. TC50 = the concentration of a drug necessary to provoke 50% of the toxic effect. The LOAEL is
the lowest observed adverse effect level, is the first tested dose or concentration of a drug that gives
a significant toxic effect. The NOAEL is no observed adverse effect level, in a tested series of
ascending doses or concentrations that is just lower than the LOAEL. Something might be a hazard
but that does not mean that there is a direct risk of this hazard. In order to asses if you are at risk the
exposure needs to be known, and many other questions that need to be answered to assess the risk.
When you stay under the concentration of NOAEL there is no risk for the individual and this thus acts
as a safety factor. To determine the ADI (acceptable daily intake) that can be taken of a drug the
NOAEL is divided by the safety factor. The therapeutic index is the dose that is toxic in 50% of the
population divided by the dose that is effective in 50% of the population. The higher the therapeutic
index the higher the safety of the compound. The margin of safety is the TD1/ED99, this can better
reflex the toxicity of a compound.
,Toxicokinetic
ADME determines the exposure to the final toxic compound. Toxification and detoxification is mainly
because of metabolism, this can be a pro but can also be a con. A toxic compound can be locally
toxic, a compound that is harmful without being absorbed. A toxic compound can be systemically
toxic, a compound that is harmful after absorption and uptake into the general circulation. But a
toxic compound can also be both. The bioavailability is the faction of the drug that reaches the
systemic circulation. Drugs enter the body via the gastrointestinal tract, skin, lung and parenteral
administration. Membranes can be passed via diffusion, passive transport, channel or carrier
mediated transport or via active transport against the
concentration in. Also an electrochemical gradient can be
used for the transport across a membrane. Physiological
carriers can be used by toxic compound to be taken up.
Exposure to a drug is what makes it toxic, high
concentration in the intestinal lumen after oral
administration, this concentration is however dependent
on the volume and the intestine content. The exposure is
also dependent upon the degree of uptake and the degree
of excretion, and of course the metabolism plays a role.
The dermal absorption happens via the skin, this can
happen via various routes. There is the intracellular route, the intercellular route and the
transappendageal route. Skin is a large surface but is little permeable the absorption thus depends
on the skin thickness, the skin damage, hydratation, temperature, metabolism in the skin and
solvent. Toxicity on the skin can happen in various ways, there can be toxicity on the skin itself,
systemic toxicity, photosensitization, metabolism in the skin or allergy. After systemic or oral
administration the skin can still be toxified due to photosensitization or because of an allergy.
Pulmonary administration is administration via the lungs. This happens via gases, vapors, aerosols
and particles. Lungs have a very large surface and there is a thin air-blood separation in the alveoli.
The barrier between air in alveolus and blood is just two thin cell layers. There is rapid circulation in
the lungs and the particle size determines the penetration into the airways. Particles that are in the
respiratory tract can be transported with mucus and removed by coughing and end up in the
gastrointestinal tract via swallowing. Particles in alveoli become, phagocytized by macrophages,
transported up with mucus, removed via lymph and possibly absorbed in the blood when they are
very small. Absorption of gases depends on the solubility of the blood, the ventilation speed and the
perfusion rate. Exposure to substances via blood and via inhalation from an external environment.
The properties of an organ will affect the distribution of the drug, these are the blood flow, the
hydrostatic pressure, the pore size in the endothelium and the presence of transporters. Most drugs
are lipophilic because they can then easily pass membranes and accumulate in fat tissue. This can
cause a slow release from the fat tissue into the systemic circulation. The exposure determines on
the uptake and excretion from cells. Accumulation happens via endogenous transporters, paraquat in
the lung via polyamine transporter and lead in intestine via Ca2+ transporter. Also toxicological
compound can cause inhibition of transporters for endogenous substances, and drug-drug
interactions will compete for the same transporter and might lead to toxicity. Distribution to the
brain happens via especially lipophilic substances, small due to pores and large by pinocytosis or
phagocytosis. The blood-brain barrier has a low permeability, few pores and glia cells cover the
basement membrane to ensure not a lot can enter. There are transporters for efflux such as the Pgp,
these will export compounds out of the brain. Distribution to the fetus is only separated by 2 thin cell
layers, there are many transporters for endogenous substances and the accumulation through
metabolism in uterus. MDR1 is one of the transporters that gets rid of the toxic compounds.
, Excretion reduces the exposure and therefore toxicity but the concentration in the bile may lead to
toxicity in bile ducts, and the excretion via the bile may lead to re-exposure in the intestine or
intestinal toxicity. Metabolism in the intestine can cause damage, precipitation in the urine may
cause kidney damage and change in excretion due to age or disease can cause accumulation in
plasma leading to toxicity. Via the kidney excretion happens via filtration and active secretion, in the
kidney however, there is active reabsorption and passive reabsorption so; the excretion is the
filtration + secretion – reabsorption. In the liver the compound are taken up via hepatocytes are then
metabolised and excreted in the bile and the metabolite is then excreted from the blood. The
metabolites from the hepatocytes can also be re-up taken by the blood and then be excreted by the
kidney. Saturation of excretion transporters can lead to accumulation and toxicity in hepatocytes.
There can be down regulation or inhibition of excretion transporters which leads to accumulation
and toxicity in hepatocytes. Down-regulation of intake transporters can lead to more toxicity
elsewhere in the body. Enterohepatic circulation increases the exposure of the organism and lastly
the bile secretion can lead to toxicity in the gut. For the lung the secretion to blood and excretion to
exhalation air depends on the solubility of compound in the blood, the volatility of the compound,
the ventilation speed and the perfusion rate.
Metabolism I:
Metabolism happens because the body protects us against foreign compound and avoiding damage
against these compounds. Barriers to do so are anatomical barriers, immunological barriers and
metabolism. Metabolism happens because the compounds that are not needed need to be
eliminated. Xenobiotics are foreign substances these need to be eliminated, this is done by
biotransformation, metabolism. Metabolism aims to make compounds more suitable for excretion
and this is mostly done by making the compound more polar. Because drugs are mostly lipophilic
they can easily enter but leaving is hard because of this lipophilicity. Drugs are often terminated of
pharmacological action by metabolism. When a compound is metabolised it may become active or
have a different active effect compared to the effect before. Metabolites can even be toxic. The
elimination can be done is several ways; unchanged excretion can happen. In this form very polar
substances are excreted, they hardly absorb in cells and dissolve well in urine and very non-polar
volatile substance, these are exhaled quickly. Another way is spontaneous metabolism and excretion,
some compound change their chemical structure continuously which is due to the pH and can be
accelerated by enzymes. The most common way is the metabolism by enzymes. Drugs are often very
lipophilic but they need to be more hydrophilic to leave the body. These hydrophobic compounds
strongly bind to proteins and re-absorb into the proximal tubules, therefore they are hardly excreted.
The gene expression is different in different organs because the transcription factors are tissue
specific, therefore not all enzymes are expressed in every tissue. Enzymes are often intended for
conversion of endogenous substrates and can also be used to metabolize a drug. This very often
means that the affinity for the endogenous compounds is high whereas the affinity for xenobiotics is
low. These enzymes also have a limited substrate specificity for drugs. Sometimes enzymes can not
specifically be involved in endogenous substrate, these often have a low affinity for their substrate
and have a broad substrate specificity. There is a lot of interaction between the metabolism of
xenobiotics and endogenous compounds. The metabolism of xenobiotics is not very efficient a higher
metabolic rate can only be reached if there is a lot of enzyme.
There are three phases in the metabolism of xenobiotics. Phase I is a small change in the molecule,
such as oxidation, reduction and hydrolysis. In phase II the metabolite is metabolised further, it is
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