ADME

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• ADME
• METABOLISM

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• ADME
• METABOLISM
• Strictly the biological breakdown (catabolism)
  or synthesis (anabolism) of compounds.

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• ADME
• METABOLISM
• Strictly the biological breakdown (catabolism)
  or synthesis (anabolism) of compounds.
• More generally - the biological modification of
  compounds.

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• Why are drugs / xenobiotics metabolised?

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• Why are drugs / xenobiotics metabolised?
• A huge variety of chemical compounds can be
  metabolised by the body

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• Why are drugs / xenobiotics metabolised?
• A huge variety of chemical compounds can be
  metabolised by the body
• a capability bestowed on us by natural selection
  for eliminating biologically active endogenous
  and exogenous compounds.

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• Metabolism of drugs is likely to result in at
  least one of the following

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• Metabolism of drugs is likely to result in at
  least one of the following
• Increased water solubility

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• Metabolism of drugs is likely to result in at
  least one of the following
• Increased water solubility
• Decreased toxicity

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• Lipophilic compounds are likely to be retained in
  the tissues, or if they get to the kidney
  tubules, reabsorbed.

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• Lipophilic compounds are likely to be retained in
  the tissues, or if they get to the kidney
  tubules, reabsorbed.
• Water soluble or ionised drugs will be readily
  excreted no modification necessary.

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• Lipophilic compounds are likely to be retained in
  the tissues, or if they get to the kidney
  tubules, reabsorbed.
• Water soluble or ionised drugs will be readily
  excreted no modification necessary.
• more usually drugs will have to be metabolised
  in order to increase their water solubility.

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• First pass effect ( pre-systemic ciculation)
• blood from mesenteric / splanchnic vasculature
  is directed straight to liver via hepatic portal
  vein.

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• First pass effect ( pre-systemic ciculation)
• blood from mesenteric / splanchnic vasculature
  is directed straight to liver via hepatic portal
  vein.
• Systemic circulation never sees much of
  absorbed drug.

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• First pass effect ( pre-systemic ciculation)
• blood from mesenteric / splanchnic vasculature
  is directed straight to liver via hepatic portal
  vein.
• Systemic circulation never sees much of
  absorbed drug.
• ..a consequence of oral dosing.

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• Enzymes responsible for many metabolic
  processes

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• Enzymes responsible for many metabolic
  processes
• Enzymes are
• Proteins
• Catalysts they speed biochemical reactions up,
  without being affected themselves

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• Enzymes responsible for many metabolic
  processes
• Enzymes are
• Proteins
• Catalysts they speed biochemical reactions up,
  without being affected themselves
• Enzymes involved in metabolism usually have broad
  specificity

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• Often there are several isoforms of each enzyme

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• Often there are several isoforms of each enzyme
• Enzymes may be constitutive, or induced

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• Enzymes can be induced by the compound itself
• (eg barbiturates, rifampin, omeprazole)

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• Enzymes can be induced by the compound itself
• (eg barbiturates, rifampin, omeprazole)
• or by ethanol, smoking, diet (barbecued foods
  containing polycyclic aromatic hydrocarbons,
  flavanoid-containing vegetables eg cabbage).

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• Enzyme induction will decrease the effectiveness
  of a number of drugs.

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• Enzyme induction will decrease the effectiveness
  of a number of drugs.
• Some compounds or dietary factors can increase
  the effectiveness of other drugs (quinidine,
  erythromycin, cimetidine, ketoconazole,
  grapefruit!) by enzyme inhibition.

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• Two main processes
• Phase I metabolism
• Phase II metabolism

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• Two main processes
• Phase I metabolism
• functionalisation. usually oxidation,
  reduction or hydrolysis.
• Phase II metabolism

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• Two main processes
• Phase I metabolism
• functionalisation. usually oxidation,
  reduction or hydrolysis.
• Phase II metabolism
• conjugation (or synthesis) reactions

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• Purposes of these processes

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• Purposes of these processes
• Phase I
• to detoxify / render the compound biologically
  inactive

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• Purposes of these processes
• Phase I
• to detoxify / render the compound biologically
  inactive
• to make compound suitable for Phase II

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• Purposes of these processes
• Phase I
• to detoxify / render the compound biologically
  inactive
• to make compound suitable for Phase II
• to a lesser extent, make the compound more water
  soluble

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• Phase II
• to make compounds more soluble (ionised
  hydrophilic) so that they can be excreted

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• Phase II
• to make compounds more soluble (ionised
  hydrophilic) so that they can be excreted
• to reduce the half-life of the active drug

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• Over all
• metabolism is likely to reduce the exposure time
  of the body to the administered compound.

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• Over all
• metabolism is likely to reduce the exposure time
  of the body to the administered compound
• ? half-life of compound.

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• Phase I
• Reactions where one or more functional groups
  are modified.

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• Phase I
• Reactions where one or more functional groups
  are modified.
• Oxidation many different types

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• Phase I
• Reactions where one or more functional groups
  are modified.
• Oxidation many different types
• e.g. O addition (eg chlorpromazine)
• de-amination (eg amphetamine)

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• Example Ethanol
• Ethanol acetaldehyde acetic acid

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• Example Ethanol
• Alcohol dehydrogenase (ADH)
  
• Ethanol acetaldehyde acetic acid

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• Example Ethanol
• Alcohol dehydrogenase Aldehyde dehydrogenase
• (ADH) (ALDH)
• Ethanol acetaldehyde acetic acid

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• Alcohol dehydrogenase is primarily located in
  the liver

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• Alcohol dehydrogenase is primarily located in
  the liver
• but also occurs in the kidney
• lung
• gastric mucosa

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• Disulfiram is administered to alcoholics

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• Disulfiram is administered to alcoholics
• it inhibits ALDH so induces nausea due to ?
  acetaldehyde.
• Alcohol dehydrogenase Aldehyde dehydrogenase
• (ADH) (ALDH)
• Ethanol acetaldehyde acetic acid

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• Ethanol in fact has 3 main routes of metabolism
• ethanol ? acetaldehyde
• In cytosol (ADH)
• In microsomes (CYP2E1)
• In peroxisomes (catalase)

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• ..then ? acetic acid (by ALDH in mitochondria)

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• ..then ? acetic acid (by ALDH in mitochondria)
• then acetic acid ? carbon dioxide H2O

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• Metabolism of other alcohols
• ADH / ALDH
• Methanol formic acid

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• Metabolism of other alcohols
• ADH / ALDH
• Methanol formic acid
• ADH / ALDH
• Ethylene glycol oxalic acid

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• Metabolism of other alcohols
• ADH / ALDH
• Methanol formic acid
• ADH / ALDH
• Ethylene glycol oxalic acid
• These metabolites are toxic.
• Treat with ethanol (why?)

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• Phase I oxidation reactions are catalysed by
  several hundred different enzymes.

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• Phase I oxidation reactions are catalysed by
  several hundred different enzymes.
• These belong to the cytochrome P-450 family.

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• These enzymes, co-factors O2
• the mixed function oxidase (MFO) system.

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• Family Isoform (e.g.) drug
• substrate (e.g.)
• CYP1 CYP1A2 theophylline
• CYP2 CYP2D6 codeine
• CYP3 CYP3A4 cyclosporine

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• CYP2D6 responsible for metabolising

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• CYP2D6 responsible for metabolising
• - b -adrenoreceptor antagonists (b-blockers)

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• CYP2D6 responsible for metabolising
• - b -adrenoreceptor antagonists (b-blockers)
• - tricyclic antidepressants

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• CYP2D6 responsible for metabolising
• - b -adrenoreceptor antagonists (b-blockers)
• - tricyclic antidepressants
• - codeine ? morphine

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• 5-10 of Caucasians are deficient in CYP2D6.

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• 5-10 of Caucasians are deficient in CYP2D6.
• Likely to result in impaired metabolism of
  b-blockers, antidepressants and lack of
  analgesic response to codeine.

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• 5-10 of Caucasians are deficient in CYP2D6.
• Likely to result in impaired metabolism of
  b-blockers, antidepressants and lack of
  analgesic response to codeine.
• Pharmacogenomics use of genetic information to
  guide drug choice.

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• Reduction
• removal of oxygen
• addition of hydrogen

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• Reduction
• removal of oxygen
• addition of hydrogen
• (eg warfarin, chloramphenicol, halothane)

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• Hydrolysis
• involves reaction with H2O to cleave off side
  chains

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• Hydrolysis
• involves reaction with H2O to cleave off side
  chains
• may be spontaneous or catalysed by enzymes (e.g.
  esterases).

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• Example 1
• H2O
• acetylsalicylic acid salicylic acid
• spontaneous

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• Example 2
• pseudocholinesterase
• bambuterol terbutaline
• (inactive) (active b-blocker)

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• Example 2
• pseudocholinesterase
• bambuterol terbutaline
• (inactive) (active b-blocker)
• Bambuterol therefore is an example of a
• pro-drug.

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• Active Phase I metabolites
• Pro-drugs Active metabolite
• codeine morphine
• prednisone prednisolone
• cortisone hydrocortisone
• sulindac sulindac sulphide

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• Active Phase I metabolites
• Pro-drugs Active metabolite
• codeine morphine
• prednisone prednisolone
• cortisone hydrocortisone
• sulindac sulindac sulphide

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• Active Phase I metabolites
• Active Drug Active metabolite
• allopurinol oxypurinol
• diazepam desmethyldiazepam
• imipramine desmethylimipramine