Biotransformation
Content
•
Chemical
pathways of biotransformation
•
Phase I
and phase II metabolism
•
Microsomal
and non-microsomal enzymes
•
First
pass metabolism
Intended Learning Outcomes
At the
end of this lecture, student will be able to
• Explain
chemical pathways of biotransformation
• Differentiate between phase I and phase II metabolism
• Outline
microsomal and non-microsomal enzymes
• Explain
the process of first pass metabolism
Biotransformation
• Alteration
of a drug within a living organism
• Metabolic
transformation: Mitochondrial, microsomal, cytosolic
• Inactive
to active: L- dopa – Dopamine
• Active
to inactive: Chloramphenicol conjugate
• Active
to active:
– More
active: Diazepam – Oxazepam
– Different
activity: Pethidine – Norpethidine
• Excretion
unchanged – Aminoglycosides
• Metabolism
: less polar, lipid soluble – more polar, water soluble
• Spontaneous
change into other substances
– Mechlorethamine
– active ethylniminium cations at slightly alkaline pH
– Atracurium
– Hoffman reaction
Prodrug
– Precursor
drug that itself has little or no biological activity
– Metabolized
to a pharmacologically active metabolite
First pass metabolism/ Presystemic metabolism
– Before
reaching systemic circulation gets metabolized
– Decreased
BA, diminished therapeutic response
– Bypassed:
IV, sublingual route
Chemical
Pathways of Biotransformation
Phase I
• Metabolite:
active/inactive
• Degradative
reactions
• Small
non polar/polar metabolite
• Mainly
microsomal
• Few
non- microsomal
Phase II
• Metabolite
inactive
• Synthetic
/conjugation reactions
• Polar
metabolite
• Mitochondrial,
microsomal, cytoplasmic
Drug
Metabolizing enzymes
Microsomal enzymes
• Located
on smooth ER, lungs, kidney, intestinal mucosa
• MFOs/
CYP450
• CYP1A1,2
• CYP3A4,5
• CYP2C8,
9
Non – microsomal enzymes
• Present
in cytoplasm, mitochondria, plasma
• MAO
• Esterases
• Amidases
• Transferases
• Conjugases
Phase I reactions – oxidations
Microsomal Oxidation
• Aromatic
hydroxylation
– Phenobarbitone
– P-hydroxy phenobarbitone
• Aliphatic
hydroxylation
– Pentobarbitone
– Hydroxy pentobarbitone
• N
– dealkylation
– Morphine
– normorphine
– Mephobarbitone
– phenobarbitone
• O
-dealkylation
– Codeine
– morphine
• S
-dealkylation
– 6-methyl
thiopurine – mercaptopurine
• S
– Oxidation
– Chlorpromazine
– Chlorpromazine sulfoxide
• N
– oxidation
– Trimethylamine
– Trimethylamine N – oxide
• Deamination
– Amphetamine
– phenylacetone derivative
• Desulfarisation
– Parathion
– paraoxon
Non – microsomal Oxidation
• Mitochondrial
oxidation
– Adrenaline
by MAO to VMA
• Cytoplasmic
oxidation
– Alcohol
by alcohol dehydrogenase to acetaldehyde
• Plasma
oxidation
– Histamine
by histaminase to IAA
Phase I reactions – Reductions
Microsomal reductions
• Nitro
reduction
– Chloramphenicol
to its arylamine metabolite
• Azo
reduction
– Protonsil
to sulfanilamide
• Keto
reduction
– Cortisone
to hydrocortisone
Non – microsomal reductions
Chloral hydrate to trichloro ethanol
Phase I reactions – Hydrolysis
Microsomal hydrolysis
Pethidine to pethidinic acid by hepatic esterase
Non microsomal hydrolysis
• Esterases,
amidases, peptidase, protease, phosphatase
• Procaine
– PABA
atropine – Tropic acid
• Hydrolysis
of beta lactam ring of penicillin
Phase II Reactions
Microsomal Conjugation
• Glucuronide
Conjugation:
• Parent
drugs/phase I metabolites
• Containing
phenolic, alcoholic, -COOH, -NH2, mercapto group
• Polar
readily excreted, often inactive
• Morphine,
paracetomol, aspirin, sulfonamide, bilirubin
Non microsomal Conjugations:
N –Acetyl Conjugation (In cytosol)
• Isoniazid,
PAS, dapsone, sulfonamides, histamine
Sulfate conjugation (In cytosol)
• Phenolic,
alcoholic, aromatic amines undergo
• Aspirin,
methyldopa, paracetamol, chloramphenicol
Aminoacid conjugation (In mitochondria)
• Aspirin,
benzoic acid, nicotinic acid
Methyl Conjugation (In cytosol)
• Many
catecholamines, histamine
Glutathione conjugation (In cytoplasm)
• Epoxides,
NO2 containing drugs, hydroxylamines
• Ethacrynic
acid, sulfobromophthalein
Ribosides & riboside phosphate
• Aspirin,
benzoic acid, nicotinic acid
Summary
• Phase
I: Degradative reactions
• Phase
II: Synthetic/ conjugative reactions
• Microsomal
enzymes: Inducible
• Prodrug:
Precursor drug that itself has little or no biological activity
• Glucuronide
conjugation is microsomal reaction
• FPM:
Before reaching systemic circulation gets metabolized
