The fate of xenobiotics in the body

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Xenobiotic[edit | edit source]

  • A substance that causes pathological changes in the body after absorption into the bloodstream
  • in other words also noxious substance or poison
  • Toxic effects:
  1. transient
  2. permanently damaging
  3. fatal

The fate of a drug in the body[edit | edit source]

Pharmacodynamics - what the poison does to the organism (effects)

Pharmacokinetics - what the organism does with the poison (toxicological analyses)

  • it includes following processes:
  1. Administration – a way xenobiotic enters the body: Inhalation – snorting – injection – per os – dermal….
Potential release of the bound active ingredient in the drug
  1. Absorption - the process of diffusion into the bloodstream
  2. Distribution - between blood and tissues and vice versa
  3. Biotransformation - a transformation of chemical structure, formation of active and inactive metabolites
  4. Elimination Routes of excretion - depend on a substance polarity: Kidneys - Intestines - Skin - Saliva - Lungs - Hair - Nails

Absorption of a drug[edit | edit source]

Speed of absorbance and absorbance rate - route of administration
  1. Intravenous – rapid and complete absorption (100%)
  2. Pulmonary inhalation – rapid and reduced absorption
  3. Parenteral administration - absorption from tissues - circulation
  4. Oral – first pass effect
Extent of xenobiotics absorption in the digestive tract
  1. Environment pH influences the drug absorption
  2. Absorption according to the acid-base properties of the drug
Stomach pH 1–3 pole B1 < 5 m2 acidic substances (aspirin)
Small intestine S1 pH 5–7 pole B2 200 m2
Small intestine S2 pH 7–8 pole B3 < 5 m2
Colon pH 7–8 pole B3 < 5 m2 base (ephedrine)
The absorbed proportion of the drug - depends on the method of administration
  • Biological availability (Bioavailability)
Proportion (%) of the drug absorbed into the bloodstream by a certain administration route in infinite time relative to i.v. administration (100%)
  • „First pass metabolism“ – „First pass effect“
    • Proportion of the drug that reaches the liver before entering the circulation, and therefore is metabolized before it expresses its pharmacological effect - reduction in bioavailability
    • Pre-systemic metabolite formation in oral administration compared to subcutaneous administration (sc.)

Distribution[edit | edit source]

Model of the body as a set of compartments

Distribution depends on
  • The polarity and size of the drug molecule
  • Binding of the drug and its metabolites to plasma proteins
  • Extent of ionization at given plasma pH
  • Blood supply to tissues, transport of the drug
  • Distribution between blood and tissues - water content of tissues
e.g.
  • Alcohol is dissolved evenly in the water throughout the body
  • Warfarin is strongly bound to plasma proteins and is only found in plasma and extracellular fluid
TISSUE % of water
muscle 76
fat 10
liver 68
kidneys 83
lungs 79
brain 75
Volume of water /body mass (l/kg)
plasma 0,04
blood 0,08
extracellular water 0,2
total body water 0,6
fat 0,2–0,35
  • The volume of total water decreases in course of individual's development.
  • Distribution volume - hypothetical quantity after distribution equilibrium is reached. Substances strongly bound to tissue proteins have high Vd and reduced plasma concentration
Vd = D/c0 nebo Vd = a/c
D – absorbed dose of a drug/chemical (i. v. dose)
c0 – initial plasma concentration (after i. v. dose)
(see reading from the semi-logarithmic kinetic curve below)
a – the current amount of the drug in the body
c – current plasma concentration
Distribution volume of substances
Vd (l) Place of occurrence of the drug
5 remains in plasma
5–20 distribution into the extracellular space
20–40 distribution into all body fluids
>40 depot in peripheral tissues

Elimination[edit | edit source]

The vast majority of xenobiotics is metabolized in the liver and excreted in the urine. Ethanol is eliminated according to zero- order kinetics. First-order kinetics mainly applies to drugs: 

− dc/dt = kel. c

Plasma elimination half-life: 

− dc/dt = kel. c 
c = exp (− kel. dt)
ln c = − kel. t

Half-life when, c = ½ c0 

ln ½ = - kel. t½
ln 2 = kel. t½
t½ = 0,693 / kel
  • In general: after 5 half-lives, 96.875% of the drug is eliminated, i.e. the organism is practically clean of the substance
  • Clearance – volume of plasma from which a substance is completely removed per unit time
[Cl] = [ volume/(mass.time) ]
  • Total clearance and clearance of individual organs - dependent on the health condition of the individual
  • Substances bound in tissues with high Vd are eliminated for a long time at a given clearance, they have a long half-life
t½ = 0,693.Vd/Cl or kel = Cl/Vd
  • SUMMARY - Important pharmacokinetic data:
kel; t½; Vd; Cl
Enterohepatic circulation
  • Xenobiotics and metabolites excreted by the bile into the intestines are reabsorbed, then they pass the liver and are again excreted into the bile, then again into the intestines……
  • This cycle is repeated until complete elimination
  • Circulation prolongs the stay of a xenobiotic in the organism and can prolong or delay toxic manifestations
  • Chemicals which are proved to enter enterohepatic circulation are found in the intestines even after parenteral administration (e.g. opiates, benzodiazepines)
Release from tissues
  • Tissue blood supply
  • Adipose tissue - little blood supply
  • Slow re-release of an accumulated drug into the blood
  • Extended elimination
e.g. Chronic marijuana abuse - depot in adipose tissue - long-term metabolite excretion


Links[edit | edit source]

Related articles[edit | edit source]

Source[edit | edit source]

  • PROKEŠ, Jaroslav. Základy toxikologie :  obecná toxikologie a ekotoxikologie. 1. edition. Prague : Galén : Karolinum, c2005. ISBN 80-7262-30-1X.
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