Download Toxicokinetics 5

Toxicokinetics
Lect 5
Factors affecting pulmonary absorption
1. Solubility of the drug in the blood
2. Particle size
Large particles are deposited in the nasal tract > 5
microns; 2-5 micron particles are deposited
mainly in the tracheobronchial region; while
particles less than 1 micron penetrate into the
alveolar sacs and absorbed into the blood
3. Water solubility
High water solubility volatile drugs are absorbed in
the nasal tract; while low water solubility drugs
will reach the bronchioles to alveoli
Airway anatomy
bronchial tree
trachea
•
•
diffusion distance: ~20 mm
total gas exchange area: ~80 m2
Airway anatomy
trachea
alveoli
capillaries
bronchial tree
•
•
diffusion distance blood/air: ~20 mm
total exchange gas exchange area: ~80 m2
Factors affecting dermal
absorption
1. Condition of the skin: Stratum corneum serves as the main
barrier. When abraded, increased absorption will result
2. Skin permeability coefficient
This represents the rate at which a particular drug penetrates
the skin
3. Body region
Not all regions of the body have the same skin thickness.
Forehead versus palm
4. Lipid solubility
The more lipid soluble the drug is the more it will be absorbed
5. Skin hydration
Rate of Absorption
• The rate of absorption may be of toxicological importance because
it is a major determinant of the peak plasma concentration and,
therefore, the likelihood of acute toxic effects.
• Transfer of chemicals from the gut lumen, lungs, or skin into the
general circulation involves movement across cell membranes, and
simple passive diffusion of the unionized molecule down a
concentration gradient is the most important mechanism.
• Lipid-soluble molecules tend to cross cell membranes easily and are
absorbed more rapidly than water-soluble ones. The gut wall and
lungs provide a large and permeable surface area and allow rapid
absorption; in contrast the skin is relatively impermeable and even
highly lipid-soluble chemicals can enter only slowly
Extent of Absorption
• The extent of absorption is important in determining the total
body exposure or internal dose, and therefore is an important
variable during chronic toxicity studies and/or chronic human
exposure.
• The extent of absorption depends on the extent to which the
chemical is transferred from the site of administration into
the local tissue, and the extent to which it is metabolized or
broken down by local tissues prior to reaching the general
circulation.
• An additional variable affecting the extent of absorption is the
rate of removal from the site of administration by other
processes compared with the rate of absorption
• Chemicals given via the gastrointestinal tract
may be subject to a wide range of pH values
and metabolizing enzymes in the gut lumen,
gut wall, and liver before they reach the
general circulation.
• The initial loss of chemical prior to it ever
entering the blood is termed first-pass
metabolism or pre-systemic metabolism; it
may in some cases remove up to 100% of the
administered dose so that none of the parent
chemical reaches the general circulation. The
intestinal lumen contains a range of hydrolytic
enzymes involved in the digestion of nutrients.
The gut wall can perform similar hydrolytic
reactions and contains enzymes that can
oxidize many drugs
Absorption and Bioavailability
• Irrespective of the reason that is responsible for the
incomplete absorption of the chemical as the parent
compound, it is essential that there is a parameter which
defines the extent of transfer of the intact chemical from the
site of administration into the general circulation.
• This parameter is the bioavailability, which is simply the
fraction of the dose administered that reaches the general
circulation as the parent compound. (The term bioavailability
is perhaps the most misused of all kinetic parameters and is
sometimes used incorrectly in a general sense as the amount
of drug available specifically to the site of toxicity).
Bioavailability
The fraction of the administered dose reaching the systemic
circulation and is thus a measure of first pass elimination
for I.V.: 100%
for non I.V.: ranges from 0 to 100%
e.g. Lidocaine bioavailability 35% due to
destruction in gastric acid and liver metabolism
First pass effect
• The first-pass effect (also known as first-pass metabolism)
is a phenomenon of drug metabolism whereby the
concentration of a drug is greatly reduced before it reaches
the systemic circulation i.e. Propranolol, Diazepam
• After a drug is swallowed, it is absorbed by the digestive
system and enters the hepatic portal system. It is carried
through the portal vein into the liver before it reaches the
rest of the body. The liver metabolizes many drugs,
sometimes to such an extent that only a small amount of
active drug emerges from the liver to the rest of the
circulatory system
• This first pass through the liver thus greatly reduces the
bioavailability of the drug
Liver vein
Systemic
circulation
Liver
Liver artery
70
Plasma concentration
Bioavailability (F)
60
50
(AUC)o
(AUC)iv
i.v. route
40
30
oral route
20
Time (hours)
10
0
0
2
4
6
8
10
Calculation of Bioavailability
• The fraction absorbed as the intact compound or bioavailability (F)
is determined by comparison with intravenous (i.v.) dosing (where F
= 1 by definition). The bioavailability can be determined from the
area under the plasma concentration–time curve (AUC) of the
parent compound , or the percentage dose excreted in urine as the
parent compound, i.e. for an oral dose: