Pharmacokinetics

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Pharmacokinetics

• David R Bell

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Concentration and toxicity
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Toxicity and concentration
concentration
In
Out
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Routes

• Input
• Oral
• Dermal
• Inhalation
• Mucous membranes
• Intravenous
• Intraperitoneal

• Output
• Urine (kidneys)
• Faeces (liver/ poor uptake)
• Exhalation
• Sweat
• Tears
• Lactation
• Hair

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Fatty compounds
Blood
Fat
In
Brain
Kidney
Other tissue
Out
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Lipophilicity
Blood
Fat
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Metabolism

• Lipophilic compounds will accumulate in fatty
  tissues--- toxicity
• Metabolism of foreign compounds tends to make
  them more hydrophilic
• Therefore, present in blood
• Subject to renal excretion

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Importance of metabolism

• Furafylline
• Drug candidate, non-toxic per se
• In clinical trials, volunteers showed severe side
  effects
• Not related to furafylline
• Related to consumption of coffee
• Furafylline specifically inhibits cytochrome P450
  1A2
• P450 1A2 metabolises and clears caffeine
• Furafylline leads to lack of clearance of
  caffeine and toxicity

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Detoxification and activation of carcinogens

• The balance
• High P450 means
• Higher production of oxidised metabolites
• Oxidised metabolites react with DNA
• More cancer
• But you get cancer after you have reproduced
• Low P450 means acute toxicity
• No chance to reproduce

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Fatty compounds
Blood
Fat
In
Brain
Kidney
Other tissue
Out
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Portals of entry
Gut drains to liver
Gut
Liver
Blood
Metabolism in liver
Metabolism in gut wall
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First-pass metabolism

• Naloxone has gt97 metabolism by the liver
• Given i.v. or sub-lingual for systemic
  administration
• Budesonide has extensive metabolism in gut and
  liver
• Insulin degraded in gut

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Organs of elimination

• Liver
• 27 of cardiac output
• 2.3 of body mass
• Excretion through bile
• Metabolism
• Kidney
• 22 of cardiac output
• 0.5 body mass
• Excretion in urine

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A model
Blood
In
Compartment 2
Out
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Volume of distribution
A
Amount of drug in body
_
V
C
Concentration of drug in blood
For a 70 kg human 5 Litres blood 16 Litres
extracellular water 42 Litres total body
water gt100 L means it is outside the blood
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Rate of elimination
Rate k Where k is a constant
Zero order kinetics
Time (hours)
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Rate of elimination
One hour- 50
One hour- 50
One hour- 50
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Rate of elimination

• Rate of elimination k blood concentration
• Where k is the first order rate constant
• The half-life is the time required for the
  concentration of compound to half
• First order kinetics

Compartment 1
kx
Out
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Rate of elimination
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Rate of elimination

• There are two elimination processes
• A fast process
• A slow process
• Best explained by two compartment model

k2x
k1x
Blood
Compartment 2
Out
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Summary

• Concentration of compound is key
• Concentration is determined by input and output
  rates
• Models of output rate
• Metabolism is key excretion route
• Physiological systems control uptake and output
  rates