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?

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:

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.

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 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

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.

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:

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 dehydrogenaseAldehyde dehydrogenase (ADH) (ALDH) Ethanol acetaldehyde acetic acid

Alcohol dehydrogenase is primarily located in the liver

but also occurs in thekidney lung gastric mucosa

Disulfiram is administered to alcoholics:

…it inhibits ALDH so induces nausea due to  acetaldehyde. Alcohol dehydrogenaseAldehyde 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  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.

These belong to the cytochrome P-450 family.

These enzymes, + co-factors + O 2 = the mixed function oxidase (MFO) system.

FamilyIsoform (e.g.)drug substrate (e.g.) CYP1CYP1A2theophylline CYP2CYP2D6codeine CYP3CYP3A4cyclosporine

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.

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 H 2 O to cleave off side chains

Hydrolysis involves reaction with H 2 O to cleave off side chains may be spontaneous or catalysed by enzymes (e.g. esterases).

Example 1: H 2 O 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-drugsActive metabolite codeinemorphine prednisoneprednisolone cortisonehydrocortisone sulindacsulindac sulphide

Active Phase I metabolites: Pro-drugsActive metabolite codeinemorphine prednisoneprednisolone cortisonehydrocortisone sulindacsulindac sulphide

Active Phase I metabolites: Active DrugActive metabolite allopurinoloxypurinol diazepamdesmethyldiazepam imipraminedesmethylimipramine