Drug metabolism

Refers to enzyme-mediated biotransformations

(detoxication) that alter the pharmacological
activity of both endogenous and exogenous
compounds.
 Drug metabolism

Drugs undergo a variety of chemical changes in the

animal organism by enzymes of the liver, intestine,
kidney, lung, plasma and other tissues.

Many enzymes take place in such biotransformations;

oxidase, hydrolase, lipase, synthetase, dehydrogenase,
etc
 Blood

CNS

Muscles

Heart
Metabolism may result in:

Pharmacologically inactive drug (detoxification).

Pharmacologically active drug

(bioactivationprodrug approach).

Change the pharmacological activity (toxic effect).

The importance of studying
drug metabolism:
Understanding the pharmacological and
toxicological activity of drugs.
The importance of shortening the drugs duration
of action.
The complications of drug-drug interactions
mainly depends on the induction or inhibition of
metabolic enzymes
 Drug metabolism
Can be divided into two distinct categories:

Phase-I:
Reactions which introduce or unmask hydrophilic
groups in the drug structure (functionalisations).

Phase-II:
Reactions which conjugate the drug or its phase-I
metabolite with a hydrophilic, endogenous species
(conjugation reactions).
 Phase-I reactions

Aliphatic hydroxylation.
Oxidation:
Oxidative Dealkylation.
Oxidative deamination.
N and S oxidation.
Alcohol/aldehyde dehydrogenase.
Reduction.
Hydrolysis.
 Phase-II metabolism
Involves the following conjugation reactions
that are catalyzed by transferase enzymes:

Glucuronidation.
Sulfation.
Amino acid conjugation.
Methylation.
Acetylation.
 Phase-I reactions
Two general types of enzyme systems take
part in these reactions:

Microsomal Mixed Function Oxidases (MFOs)

Flavoprotein, NADPH-monooxygenase
Cytochrome P450

Non-cytochrome oxidizing enzymes.

Xanthine oxidase
Alcohol/aldehyde dehydrogenase
General features of Cytochrome P-450

A large number of families (at least 18 in mammals)

of cytochrome P-450 (abbreviated CYP) enzymes
exists as well as many subfamilies.
each member catalyzes the biotransformation of a
unique group of drugs
some overlap in the substrate specificities.
CYP 450
Families and subfamilies

Foye's principles of medicinal chemistry

 CYP Biotransformations

Chemically diverse small molecules are converted,

generally to more polar compounds
Reactions include:

Aliphatic hydroxylation, aromatic hydroxylation

Dealkylation (N-,O-, S-)
N-oxidation, S-oxidation
Deamination
Dehalogenation
 Oxidative Phase-I involving
cytochrome P-450 enzymes:
Aliphatic hydroxylation:
Mainly occur on the ultimate () or penultimate
(-1) carbon atom in the structure.
Also it occurs at an activated carbon atom, that is
next to sp , sp2 carbons:
 Oxidative Phase-I involving
cytochrome P-450 enzymes:
Aliphatic hydroxylation:
Mainly occur on the ultimate () or penultimate
(-1) carbon atom in the structure.
Also it occurs at an activated carbon atom, that is
next to sp , sp2 carbons:
 Oxidative Phase-I involving
cytochrome P-450 enzymes:
Aromatic hydroxylation:
 Aromatic epoxidation:

DNA
 Oxidative Phase-I involving
cytochrome P-450 enzymes:
Alkene epoxidation:
 Glutathione conjugation

For electrophilic drugs and metabolites:

Detoxication by glutathione adduct
formation
 Glutathione conjugation

Toxicity of aromatic compounds came from

the formation of arene oxide during the
metabolism that will be attacked by
endogenous nucleophile such as proteins,
DNA or RNA.
Glutathione conjugation
 O-dealkylation:
 N-dealkylation:
N-dealkylation
 Oxidative Phase-I involving
cytochrome P-450 enzymes:
Oxidative deamination:
 Oxidative Phase-I involving
cytochrome P-450 enzymes:

N-oxidation:
Mostly for primary and secondary amines as well
as aromatic amines:
This gives N-oxide that will be rapidly converted to
hydroxylamines.
 Hydrolytic phase-I metabolism

By non-specific esterase and amidase enzymes

that present in plasma, gut, liver and kidney.

It has a beneficial role in most of prodrugs

that after hydrolysis inside the body release
the active form of the drug.
 Ester vs. Amide bond
Ester bond is relatively weaker than amide bond,
it will be rapidly hydrolyzed by esterase
enzyme
Nucleophilic attack of hydroxide anion
on ester and amide
 Example

Procaine Procainamide
Short acting local anesthetic Long acting antiarrhythmic

T1/2 = 40-84 second T1/2 = 2.5-4.5 hr

 Hydrolytic phase-I metabolism

Examples of prodrugs activated by hydrolytic

enzymes:

Dipivefrine: is a di-tertbutylcarboxy ester of

adrenaline. More lipophilic better penetration
through the corneal membrane.then will be
hydrolyzed to give the active form (adrenaline)
Why Dipifevrine has been prepared?

Adrenaline is a polar drug.difficult access into the

ocular cavity.
Adrenaline has a generalized adrenergic effect.
Many side effects such as increase blood pressure,
heart rate and bronchodilation.
Dipifevrine is more lipophilic, better penetration
localized effect.
 Other phase-I metabolic enzymes

Alcohol dehydrogenase and aldehyde

dehydrogenase:
 Other phase-I metabolism
Heterocyclic ring oxidation:

S-dealkylation:
 Other phase-I metabolism
Sulfoxidation: by flavin monooxygenase
 Other phase-I metabolism
Azoreduction:

Antibacterial action Anti-inflammatory action

 General notes regarding phase-I
metabolism
Hydrolysis normally catalyzed by
carboxylesterases:
Cholinesterase. Hydrolyzes choline-like esters (such
as succinylcholine), procaine and acetylsalicylic acid.

Arylcarboxyesterase.
Liver carboxyesterase
Zwitter ionic
Polar
Easily excreted
 General notes regarding phase-I
metabolism
Esters that are sterically hindered are
hydrolyzed more slowly and may be appeared
unchanged in urine:
 General notes regarding phase-I
metabolism
Amides are more stable to hydrolysis than
esters.large fraction of amide containing
drugs are normally excreted unchanged.
Procaine has a short duration lidocaine has a long duration
of anesthesia of anesthesia
Nucleophilic attack of HO-
 Aromatic hydroxylation

The least substituted aromatic ring will be

favorably oxidized, especially at the least
hindered carbon atom

The activated ring will be better oxidized (the ring

bearing an electron donating group)
 The least substituted aromatic ring will be favorably
oxidized, especially at the least hindered carbon atom
 The activated ring will be better oxidized (the
ring bearing an electron donating group)

No aromatic hydroxylation