The fate of xenobiotics in the body

`Xenobiotic

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

The fate of a drug in the body
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….
 * 2) Absorption - the process of diffusion into the bloodstream
 * 3) Distribution - between blood and tissues and vice versa
 * 4) Biotransformation - a transformation of chemical structure, formation of active and inactive metabolites
 * 5) Elimination Routes of excretion - depend on  a substance polarity: Kidneys - Intestines - Skin - Saliva - Lungs - Hair - Nails

Absorption of a drug

 * passive by diffusion or
 * by active transport


 * 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


 * 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
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

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)
 * 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
 * (see reading from the semi-logarithmic kinetic curve below)

a – the current amount of the drug in the body c – current plasma concentration

Elimination
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

[Cl] = [ volume/(mass.time) ] t½ = 0,693.Vd/Cl or kel = Cl/Vd kel; t½; Vd; Cl
 * 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
 * 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
 * SUMMARY - Important pharmacokinetic data:


 * 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


 * Summary - disposition of a drug in the organism

Related articles

 * Toxicity, effects of noxious substances
 * Introduction to toxicology
 * Pharmacodynamics
 * Pharmacokinetics