Pharmacology 3b - Drug Metabolism
Anil Chopra
1. To understand the general principals of xenobiotic (foreign chemical)
biotransformation.
2. Be able to describe the routes and biochemistry of Phase I metabolism.
3. Be able to describe the routes and biochemistry of Phase II metabolism.
4. To understand the importance of drug metabolism in pharmacology.
- Xenobiotics (i.e. foreign molecules) are generally lipophilic.
- Metabolism tends to reduce or eliminate pharmacological/toxicological activity.
- Metabolism converts lipophilic chemicals to polar derivatives (readily excreted).
The main site for “first pass” metabolism is the liver. It can however occur in other
organs.
Prodrugs are drugs which are inactive unless they are metabolised by the body e.g. LDOPA  Dopamine.
Phase I Metabolism
At this stage oxidation, reduction and hydrolysis take place. Oxidation and reduction
create new functional groups, and hydrolysis unmasks them. Generally this inactivates
chemicals (however it can activate some prodrugs). The polarity of the drug is not often
changed.
In the liver it is mainly mediated by cytochrome P450. Numerous isoforms of P450 are
present and each with different and overlapping substrate specificities – about 12 count
for hepatic drug metabolism.
E.g. cytochrome P450 metabolism
RH + NADPH + O2 + H+ ====Cytochrome P450====> ROH + NADP+ + H2O
E.g. alcohol metabolism
Phase II Metabolism
A number of different reactions can occur in phase II metabolism. All of these use
enzymes and also require a high energy interemediate:
Glucuronidation: Glucuronyl transferase
Acetylation: Acetyl transferase
Amino acid conjugation: Acyl transferase
Methylation: Glutathione-S-transferase
Sulphation: Sulphotransferase
Glutathione conjugation: methyl transferase
This is CONJUGATION. Once a drug has been conjugated, it is almost always less
active and polar (and therefore ready for excretion).
Effects of Metabolism
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The biological half-life of the chemical is decreased.
The duration of exposure is reduced.
Accumulation of the compound in the body is avoided.
Potency/duration of the biological activity of the chemical can be altered.
The pharmacology/ toxicology of the drug can be governed by its metabolism.
First pass metabolism is extensive metabolism in the liver before the drug reaches the
systemic circulation after being taken orally.
 Repeated administration of some drugs increases the synthesis of cytochrome-P450
(enzyme induction). This increases the rate of metabolism of this drug and others.
 Some drugs inhibit microsomal activity and so act to increase the action of a drug –
enzyme inhibition
 Drug to dug interactions and genetic polymorphisms, age and some diseases
especially those affecting the liver can also affect metabolism
 Sometime reactive products of metabolism are toxic to various organs such as the
liver. Paracetamol normally undergoes glucuronidation and sulphation, however with
a high dose the livers stores of glutathione become depleted and a toxic metabolite
accumulates