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
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