Dr. Phil Rowe Reader in Pharmaceutical Computing

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Dr. Phil RoweReader in Pharmaceutical Computing

• School of Pharmacy Chemistry
• John Moores University
• Liverpool

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Pharmacokinetics lecture 1Contents ...

• What is Pharmacokinetics
• Absorption
• Distribution

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Pharmacokinetics

• Drug movement (Greek)
• The movement of drugs
• Into
• Around
• Back out of
• the body

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ADME

• Absorption
• Distribution
• Metabolism
• Excretion

Elimination
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Absorption

• Three mechanisms by which drugs may cross
  membranes
• Passive diffusion
• Facilitated diffusion
• Active transport
• Passive diffusion MUCH more common than any of
  the others.

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Passive diffusion
DRUG
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Requirements for passive diffusion

• Water solubility
• Lipid solubility

• Almost all drugs are sufficiently water soluble
  to undergo passive diffusion, but some do lack
  the necessary lipid solubility.
• In practice, passive diffusion depends mainly on
  lipid solubility.

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Efficiency of passive diffusion
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Facilitated diffusion
DRUG
Selective gateway allows entry of one group of
molecules, but excludes all others.
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Active transport
DRUG
Structurally selective. Energy requiring Can
operate against the concentration gradient
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Specificity

• Passive diffusion
• Non-specific. Anything lipid soluble

• Facilitated diffusion
• Active transport
• Structurally specific groups of chemicals that
  fit a carrier molecule

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Specificity
Few drugs handled by facilitated or active
transport
A molecule can only be handled by facilitated or
active transport if the body contains a suitable
carrier, so it is not surprising that very few
drugs use such mechanisms. There are some
examples. e.g. L-DOPA and gabapentin are
transported into the brain by the Large neutral
Amino Acid Transporter (LAT1)
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P-glycoproteins
(Glycoproteins proteins with carbohydrates
attached)
Gut contents
P-gp in the apical cell membrane (facing the gut
contents). Substances are absorbed, but then
actively pumped back into the gut contents
(Efflux). ATP dependent.
Apical surface
Intestinal epithelial cell
Basolateral surface
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Location of P-glycoproteins
OrganIntestineLiverKidneyBrain
FunctionPrevent absorptionExcretion into
bileExcretion into urinePrevent entry from
blood into brain
Generally a defensive mechanism against foreign
substances
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Examples of substances where intestinal
absorption is opposed by P-gp mediated efflux
Celiprolol Beta blockerCyclosporin
ImmunosuppressantDexamethasone
GlucocorticoidIvermectin AnthelminticVerapami
l AntihypertensiveVincristine Cytotoxic
Wide range of drug groups and chemical structures
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Induction and inhibition of P-gp
InductionExample - Rifampicin increase the
amount of P-gp in the intestinal epithelium.
Reduces absorption of other substances. Inhibition
Example - Large enough dose of verapamil will
saturate the P-gp. Other substances then
absorbed more easily. Has been suggested as a
means to increase absorption of problem molecules.
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Distribution
Kidneys
Blood
Etc.
Fat
Liver
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Factors influencing distribution of a drug

• Ability to undergo passive diffusion (Already
  described)
• Binding to macromolecules
• Ion trapping
• P-glycoproteins (Already described)

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Plasma protein binding
Blood
Cell
Drug
Drug
Drug.Protein
Lipid
Total drug conc in blood greater than in cell.
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Intra-cellular binding
Blood
Cell
Drug
Drug
Drug.Protein Lipid Nucleic
acid
Lipid
Total drug conc in blood lower than in cell.
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Overall binding
Blood
Cell
Drug
Drug
Drug.Protein
Drug.Protein Lipid Nucleic
acid
Lipid
Balance depends upon relative binding affinity in
blood and tissues.
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Ion trapping
Stomach (Acid)
Blood (Neutral)
Lipid
Basic drugs accumulate in acidic
environments. (Acidic drugs accumulate in basic
environments.)
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Terms with which you should be familiar ...
Pharmacokinetics ADME Absorption
Passive diffusion Distribution
Faciliated diffusion Metabolism
Active transport Excretion
P-glycoproteins Elimination
Ion trapping
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What you should be able to do

• Distinguish between metabolism and excretion
• Describe the characteristics of passive
  diffusion, facilitated diffusion and active
  transport
• Predict whether a given molecule will easily
  undergo passive diffusion
• Describe the function of P-glycoproteins
• Identify the factors that may influence the
  distribution of a given drug