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
(bioactivation…prodrug 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 drug’s 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 (ω) or penultimate
(ω-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 (ω) or penultimate
(ω-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
Short acting local anesthetic
Procainamide
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
of anesthesia
lidocaine has a long duration
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