METABOLISM

Drug metabolism often takes place in the liver but metabolism can take place elsewhere such
as, in the lungs or the gut.

The fact that most drugs get metabolized by the liver is very important for
pharmacokinetics because drugs given orally maybe metabolized by the liver before they
reach the systemic circulation this phenomenon is known as First pass metabolism.

sometimes first pass metabolism is so dramatic that it necessitates giving a drug

intravenously as giving orally would lead to significantly less active drug in the systemic
circulation.

Biochemistry of drug metabolism

(in particular the actions of cytochrome P450 ENZYMES):
Which often abbreviated CYP, these cytochrome p450 enzymes are abundant
in the liver and different types metabolize different drugs. For example,
CYP 1A2 metabolizes caffeine whereas CYP 2E1 metabolizes alcohol.
Cytochrome P450 enzymes metabolize drugs through a variety of processes
these include,
1.oxidation
2.hydrolysis
3.hydroxylation

Here we have a drug and hydrogen attached to it, this

hydrogen is going to be the target of the cytochrome P450
enzyme , through the process of hydroxylation the
cytochrome p450 enzyme has turned the hydrogen into a
hydroxyl group (phase 1)
-

but metabolism does not stop there the presence of this

Is new hydroxyl group creates a target for much larger
molecules to be attached.
there many enzymes which can act upon this newly formed
group for example, UDP- glucuronosyltransferases.
 polar group

±
through the action of UDP-glucuronosyltransferases a large glucuronic acid group is attached to the
drug this is the same process that happens in bilirubin metabolism (phase 2), the glucuronic acid
group has many polar groups attached to it namely three hydroxyl groups and carboxylic acid group
this makes the molecule extremely water soluble or hydrophilic thus drug can be easy filtered and
excreted by the kidneys.

Example:
Aspirin or (acetylsalicylic acid)

The phase 1 metabolism of the aspirin involves, a cytochrome P450 hydrolyzing the aspirin
molecule and the resultant product is salicylic acid , as salicylic acid is the active drug in
other words aspirin needs to be metabolized before it has any effect because of this we
call aspirin a (prodrug).

Salicylic acid can then be acted upon by UDP-glucuronosyltransferases to attach the glucuronic acid
group in place of the hydroxyl group , now the product can easily be excreted by the kidneys