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zChemical Pathways of Drug Metabolism: Phase 1/ II Reactions
Biochemical and Molecular Principles of Drug Action Biochemical and Molecular Principles of Drug Action
21
Pharmacology
Professional
03/03/2012
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Term
Microsomal and Non-microsomal
 Definition
 Microsomal
• CYP’s
 Non-microsomal
• Oxidases
• Dehysrogeases
Term
Pre-systemic Drug Metabolism
 Definition
 GI Tract
 Liver
Term
systemic Drug Metabolism
 Definition
 Systemic circulation
 Other organs
Term
Drug Metabolism : Enzymes: CYPs
 Definition
o Organ Location: Liver, kidneys, lungs and intestine
o Cellular Location: Endoplasmic reticulum (ER)
o Catalyzes oxidation reactions
o Classified based on family, subfamily and isoforms
Term
Polymorphic CYPs relevant for drug metabolism
 Definition
o 1A2
o 2A6
o 2C8
o 2C9
o 2C19
o 2D6
o 2E1
 Asian variants
 Effected by smoking
Term
Phase I
 Definition
 Introduction of polar functional groups
 Increase in water solubility
 Drugs could be eliminated after Phase I if or could undergo Phase II reactions
 Examples
• Oxidation
o Hydroxylaton
o Oxidation
o Dealkylation
o Deamination
• Reduction
• Hydrolysis
Term
Phase II
 Definition
 Involves conjugation with endogenous molecules such as amino acids, sulfate, glutathione etc.
 The purpose is to further increase water solubility (exception : methylation)
 Examples
• Methylation
• Glycine conjugation
• Sulfation
• Glutathione conjugation
• Acetylation
Term
Oxidation
 Definition
 95% of oxidation reactions are catalyzed by CYP enzymes
 Non-CYP enzymes catalyzing oxidation are:
• Alcohol dehydrogenase
• Aldehyde dehydrogenase
• Flavin containing monooxygenase –FMO (Important enzyme for oxidation of xenobiotics containing N or S)
• Xanthine Oxidase
o Treatment of gout (target)
• Amine Oxidase
• Aromatases
o Target for best and ovarian cancer
Term
Oxidation : Hydroxylation
 Definition
 Introduction of hydroxyl groups to an aliphatic or aromatic structure
• CYP2C8/CYP2C9 - aliphilic (Adds primary or secondary OH)
• CYP2C9 – aromatic (Adds to least hindered
Term
Oxidation : N-Oxidation and S-Oxidation
 Definition
 N and S groups are oxidized to form corresponding oxides
 Usually oxide derivative undergoes further reactions
 N- oxidation
• FMO
 S- oxidation
• FMO
Term
Oxidation : Dealkylation
 Definition
 Involves losing of alkyl group attached to N, O or S
• CH3, CH3CH2, CH3CH2CH2, (CH3)2CH2, CH3CH2CH2CH2
• Des
o Desmethyl – Loss of a methyl
• Nor
o Same as des
• N- Dealkylation – CYP2C19
• O-Dealkylation – CYP2D6
• S-Dealkylation – CYP
Term
Oxidation : Deamination
 Definition
 Involves losing of primary amine group and formation of ketones or acids
 Commonly seen in metabolism of neurotransmitters
 Catalyzed by Monoamine Oxidases (MAO)
Term
Reduction
 Definition
 Not as common as oxidative reactions
 Generally the CYP450 enzymes are used in the presence of NADPH
 Three major types of reduction reactions pertinent to drug metabolism:
• Azo-reduction
o Azoreductase a.k.a. CYP450’s
o N=N -> NH2 + H2N
• Niro-reduction
o NO2 -> NH2
• Reduction of ketones
o =O -> OH
Term
Hydrolysis
 Definition
 Common metabolic transformation of drugs containing esters or amides
 Esterases and amidases are mainly responsible for the hydrolysis
Term
Methylation
 Definition
 Adds Methyl group to OH
• OH -> OCH3
• Methylation and acylation are phase II reactions but decreases water solubility
Term
Glycine conjugation
 Definition
• Adds Glycine
Term
Conjugation with Glutathione (GSH)
 Definition
 3. Glutathione Conjugation:
• Involves replacement of electrophilic substitution in xenobiotic with glutathione
• GSH also acts as a free radical scavenger
Term
Sulfate Conjugation
 Definition
 Commonly seen in the biotransformation of steroid hormones, catecholamine neurotransmitters, bile acids and phenolic drugs
Term
Glucuronic acid conjugation
 Definition
most common route of phase II metabolism
 Adds hydrophilic groups to “handles” created in Phase I metabolism
 Glucuronides are less reactive/active than their parent molecules in most cases
 Typically, –OH, -NH2 groups undergo this process (sometimes COOH)
 Readily eliminated (mainly by kidneys)
 UDP= Uridine diphosphate
 UGT= Uridine Glucoronyl transferase
 If added to a carboxylic acid, dissolves in urine
Term
Acetylation
 Definition
 Adds AC to
 NH2 -> H3CCON
 Fast Acetylators and slow acetylators
 Methylation and acylation are phase II reactions but decreases water solubility
Term
Drug Metabolism : Chemical Pathways: Phase II
 Definition
o Conjugation Reactions
o Enzymes are called as transferases
o Methylation
o Glycine conjugation
o Conjugation with Glutathione (GSH)
o Sulfation
o Glucoridination
o Acetylation
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