ADME

METABOLISM

ADME

METABOLISM

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

ADME

METABOLISM

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

• More generally - the biological modification of compounds.

Why are drugs / xenobiotics metabolised?

Why are drugs / xenobiotics metabolised?

• A huge variety of chemical compounds can be metabolised by the body;

• 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.

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

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

• Increased water solubility

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

• Increased water solubility

• Decreased toxicity

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

• 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.

• 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.

First pass effect ( = pre-systemic ciculation):

• blood from mesenteric / splanchnic vasculature is directed straight to liver via hepatic portal vein.

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.

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.

• Enzymes – responsible for many metabolic processes

Enzymes – responsible for many metabolic processes

Enzymes are:– Proteins– Catalysts: they speed biochemical reactions up,

without being affected themselves

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

• Often there are several isoforms of each enzyme

• Often there are several isoforms of each enzyme

• Enzymes may be constitutive, or induced

Enzymes can be induced by the compound itself

• (eg barbiturates, rifampin, omeprazole)

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).

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

• 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.

• Two main processes:

• Phase I metabolism

• Phase II metabolism

• Two main processes:

• Phase I metabolism– “functionalisation”. usually oxidation, reduction

or hydrolysis.

• Phase II metabolism

• Two main processes:

• Phase I metabolism– “functionalisation”. usually oxidation, reduction

or hydrolysis.

• Phase II metabolism – conjugation (or synthesis) reactions

“Purposes” of these processes:

“Purposes” of these processes:

• Phase I: – to detoxify / render the compound biologically

inactive;

“Purposes” of these processes:

• Phase I: – to detoxify / render the compound biologically

inactive;

– to make compound suitable for Phase II

“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

- Phase II:

– to make compounds more soluble (ionised; hydrophilic) so that they can be excreted;

- Phase II:

– to make compounds more soluble (ionised; hydrophilic) so that they can be excreted;

– to reduce the half-life of the active drug

Over all:

- metabolism is likely to reduce the exposure time of the body to the administered compound.

Over all:

- metabolism is likely to reduce the exposure time of the body to the administered compound

half-life of compound.

Phase I:

Reactions where one or more functional groups are modified.

Phase I:

Reactions where one or more functional groups are modified.

Oxidation – many different types:

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)

Example: Ethanol:

Ethanol acetaldehyde acetic acid

Example: Ethanol:

Alcohol dehydrogenase (ADH)

Ethanol acetaldehyde acetic acid

Example: Ethanol:

Alcohol dehydrogenase Aldehyde dehydrogenase

(ADH) (ALDH)

Ethanol acetaldehyde acetic acid

Alcohol dehydrogenase is primarily located in the liver

Alcohol dehydrogenase is primarily located in the liver

but also occurs in the kidney

lung

gastric mucosa

Disulfiram is administered to alcoholics:

Disulfiram is administered to alcoholics:

…it inhibits ALDH so induces nausea due to acetaldehyde.

Alcohol dehydrogenase Aldehyde dehydrogenase

(ADH) (ALDH)

Ethanol acetaldehyde acetic acid

• Ethanol in fact has 3 main routes of metabolism:

ethanol acetaldehyde– In cytosol (ADH)– In microsomes (CYP2E1)– In peroxisomes (catalase)

..then acetic acid (by ALDH in mitochondria)

..then acetic acid (by ALDH in mitochondria)

…then acetic acid carbon dioxide + H2O

Metabolism of other alcohols:

ADH / ALDH

Methanol formic acid

Metabolism of other alcohols:

ADH / ALDH

Methanol formic acid

ADH / ALDH

Ethylene glycol oxalic acid

Metabolism of other alcohols:

ADH / ALDH

Methanol formic acid

ADH / ALDH

Ethylene glycol oxalic acid

These metabolites are toxic.

Treat with ethanol (why?)

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

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

These belong to the cytochrome P-450 family.

These enzymes, + co-factors + O2

= the mixed function oxidase (MFO) system.

• Family Isoform (e.g.) drug

substrate (e.g.)

• CYP1 CYP1A2 theophylline• CYP2 CYP2D6

codeine• CYP3 CYP3A4 cyclosporine

CYP2D6 responsible for metabolising:

CYP2D6 responsible for metabolising:

-adrenoreceptor antagonists (-blockers)

CYP2D6 responsible for metabolising:

-adrenoreceptor antagonists (-blockers)

- tricyclic antidepressants

CYP2D6 responsible for metabolising:

-adrenoreceptor antagonists (-blockers)

- tricyclic antidepressants

- codeine morphine

• 5-10% of Caucasians are deficient in CYP2D6.

• 5-10% of Caucasians are deficient in CYP2D6.

• Likely to result in impaired metabolism of -blockers, antidepressants; and lack of analgesic response to codeine.

• 5-10% of Caucasians are deficient in CYP2D6.

• Likely to result in impaired metabolism of -blockers, antidepressants; and lack of analgesic response to codeine.

• Pharmacogenomics – use of genetic information to guide drug choice.

Reduction

• removal of oxygen

• addition of hydrogen

Reduction

• removal of oxygen

• addition of hydrogen

(eg warfarin, chloramphenicol, halothane)

Hydrolysis

• involves reaction with H2O to cleave off side chains

Hydrolysis

• involves reaction with H2O to cleave off side chains

• may be spontaneous or catalysed by enzymes (e.g. esterases).

Example 1:

H2O

acetylsalicylic acid salicylic acid

=spontaneous

Example 2:

pseudocholinesterase

bambuterol terbutaline

(inactive) (active -blocker)

Example 2:

pseudocholinesterase

bambuterol terbutaline

(inactive) (active -blocker)

Bambuterol therefore is an example of a

pro-drug.

Active Phase I metabolites:

Pro-drugs Active metabolite

codeine morphine

prednisone prednisolone

cortisone hydrocortisone

sulindac sulindac sulphide

Active Phase I metabolites:

Pro-drugs Active metabolite

codeine morphine

prednisone prednisolone

cortisone hydrocortisone

sulindac sulindac sulphide

Active Phase I metabolites:

Active Drug Active metabolite

allopurinol oxypurinol

diazepam desmethyldiazepam

imipramine desmethylimipramine