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Definition of Metabolism
Metabolism is defined as the sum total of all chemical reactions that occur in the body.
In Other WordsMetabolism of drugs is defined as the
conversion from one chemical form to another.
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Converting lipophilic to water soluble compounds
Xenobiotic
Reactive intermediate
Conjugate
Phase I - Activation
Phase II - Conjugation
Excretion
Lipophilic
(non-polar)
Water soluble(polar)
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ORGAN SITES OF DRUG METABOLISM
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Organ Sites of Drug Metabolism
• Liver
• Small intestine
• Kidney
• Skin
• Lungs
• Plasma
• All organs of the body
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CELLULAR SITES OF DRUG METABOLISM
CELLULAR SITES OF DRUG METABOLISM
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Cellular Sites Of Drug Metabolism
• Cytosol
• Mitochondria
• Lysosomes
• Smooth endoplasmic reticulum (microsomes)
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Drug metabolising enzymes
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The enzymes are broadly divided into two categories
Microsomal
Non Microsomal
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Hepatic microsomal enzymes (oxidation, conjugation)
Extrahepatic microsomal enzymesExtrahepatic microsomal enzymes (oxidation, conjugation)(oxidation, conjugation)
Hepatic non-microsomal enzymesHepatic non-microsomal enzymes (acetylation, sulfation,GSH, (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase,alcohol/aldehyde dehydrogenase,hydrolysis, ox/red)hydrolysis, ox/red)
Drug Metabolism
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PATTERNS OF DRUG METABOLISM
1. PARENT MOLECULE PHASE 1 METABOLISM METABOLITE
2. PHASE 1 METABOLITE PHASE 2 METABOLISM METABOLITE
3. PARENT MOLECULE PHASE 2 METABOLISM METABOLITE
4. PHASE 2 METABOLITE PHASE 1 METABOLISM METABOLITE
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PHASES OF DRUG METABOLISMPHASES OF DRUG METABOLISM
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Phase I Metabolism
R ROH R RCOOH
R RSH R RNH2
Polar groups are exposed on or introduced to a molecule
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Phase I Reactions
OXIDATION
REDUCTION
HYDROLYSIS
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Oxidative Reactions
1. Oxidation Of Aromatic Carbon Atoms
acetanilide p-hydroxyacetanilide
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2.Oxidation of olefins(C=C bond)
Carbamazepine Carbamazepine-10,11-epoxide
Trans-10,11-dihydroxy carbamazepine
H2OH2O
Epoxidehydrase
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3.Oxidation of Benzylic Carbon Atom
Tolbutamide Primary Carbinol Corresponding aldehyde
CorrespondingCarboxylic acid
2OH
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4.Oxidation of Allylic Carbon Atoms
Hexobarbital3-hydroxy Hexobarbital
Allylic Carbon Atom
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5.Oxidation of Carbon Atoms Alpha to Carbonyls and imines
OH
Diazepam3-Hydroxy diazepam
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6.Oxidation of Aliphatic Carbon Atoms
5-Hydroxy Valproic Acid(minor product)
4-Hydroxy ValproicAcid(major product)
OH
HO
ω -Oxidation
ω-1 Oxidation
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7.Oxidation of Alicyclic Carbon Atoms
OH
Minoxidil 4’-Hydroxy minoxidil
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8.Oxidation of carbon-heteroatom systems
A.Carbon-Nitrogen systemsi. N-Dealkylationii. Oxidative Deaminationiii. N-Oxide Formationiv. N-Hydroxylation
B.Carbon-Sulfur Systems
i. S-Dealkylationii. Desulfurationiii. S-Oxidation
C.Carbon-Oxygen Systems
i. O-Dealkylation
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A.Carbon-Nitrogen systems
i. N-Dealkylation
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ii. Oxidative Deamination
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iii. N-Oxide Formation
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iv. N-Hydroxylation
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B.Carbon-Sulfur Systems
i. S-Dealkylation
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ii. Desulfuration
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iii. S-Oxidation
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C.Carbon-Oxygen Systems
i. O-Dealkylation
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9.Oxidation of Alcohol,Carbonyl and Carboxylic Acid.
AlcoholDehydrogenase
Aldehyde Dehydrogenase
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Reductive Reactions
1. Reduction of Carbonyls (Aldehyde and Ketones)
H2O
Aldehyde
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Ketones
MethadoneMethadol
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2.Reduction of Nitro Compounds
R N O 2 R N H 2
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3.Reduction of Azo Compounds
R N = N R ' R N H 2 + R ' N H 2
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Hydrolytic Reactions1.Ester Hydrolysis
R C O O R ' R C O O H + R ' O H
Enalaprit
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2.Amide Hydrolysis
R C O N R ' R " R C O O H + H N R ' R "
+ NH2CH2CH2N(C2H5)2
Procainamide
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CarbamazepineIminostilbine
H
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3.EPOXIDE HYDROLASE
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PHASE II METABOLIC PATHWAYS
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D+ ENDOX DX+ENDO
PHASE 2 METABOLISM
A molecule endogenous to the body donates a portion of itself to the foreign molecule
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PHASE II REACTIONS Glucuronidation
Sulfate Conjugation
Acetylation
Glycine Conjugation
Methylation
Transulfuration
Glutathione Conjugation
Mercapturic Acid Synthesis
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GLUCURONIDATION
Uridine-5’diphospho--D-glucuronic Acid
The microsomal enzyme glucuronyl transferase conducts the donation of glucuronic acid from the endogenously synthesized UDPGA to various substrates to form glucuronide conjugates. Examples of such substrates are morphine and acetaminophen.
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SYNTHESIS OF UDPGA
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Glucuronidation of Benzoic Acid
UGT= UDP--D-Glucuronsyltransferase
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Glucuronidation of Aniline
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Glucuronidation of p-Hydroxyacetanilid
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SULFATE CONJUGATION
• Conducted by the soluble enzyme sulfotransferase• Endogenous donor molecule to conjugation is
3’-phosphoadenosine-5’-phosphosulfate (PAPS)• Conjugates are ethereal in character• Noninducible
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3’-Phosphoadenosine-5’-phosphosulfate (PAPS)
The cytosolic enzyme sulfotransferase conducts the donation of sulfate from the endogenously synthesized PAPS to various substrates to form sulfate conjugates. An example of such substrate is acetaminophen.
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SYNTHESIS OF PAPS
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Sulfate Conjugation of p-Hydroxyacetanilid
PAP: 3’-phosphoadenosine- 5’-phosphate
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AMINO ACID CONJUGATION
RCOOH + CoA-SHAcid:CoA ligase
RCO-S-CoA
RCO-S-CoA + NH2CH2COOH
RCONHCH2COOH
N-acyl transferase
ATP
Glycine
Glycine conjugate
(mitochondria)
Acyl CoA
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Salicycluric Acid is the Glycine Conjugate of Aspirin
Salicyluric acid, the glycine conjugate of salicyclic acid, is the main metabolite of aspirin. Approximately 76% of aspirin is metabolized through amino acid conjugation.
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N-ACETYLATION
• A soluble enzyme• Isoniazid is a substrate• Genetic variation occurs
– Some individuals are fast acetylators– Some individuals are slow acetylators
• Acetyl coenzyme A is the endogenous donor molecule
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Acetyl CoA
Various acetylases, for examples, choline acetylase and N-acetyl transferase, all soluble enzymes, conduct the transfer of the acetyl group of acetyl CoA to various substrates. For example, N-acetylation of isoniazid. Genetic polyporphism occurs with N-acetyltransferase.
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N-Acetyltransferase
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METHYLATION
S-Adenosylmethionine
Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT) conducts the donation of the methyl group from the endogenously synthesized SAM to various substrates to form methylated conjugates. Norepinephrine is N-methylated by PNMT to form epinephrine. Norepinephrine, epinephrine, dopamine, and L-DOPA are O-methylated by COMT.
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Methyltransferases
• A family of soluble enzymes that conducts
– N-methylation; N-CH3
– O-methylation; O-CH3
– S-methylation; S-CH3
• S-adenosylmethionine (SAM)is the endogenous donor molecule. It is demethylated to S-adenosylhomocysteine
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N-Methyltransferases
PNMT- Phenylethanolamine-N-methyltransferase
Norepinephrine EpinephrinePNMTSAM
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O-Methylation Of Catecholamines
COMT- catechol-O-methyltransferase
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O-Methylation of Norepinephrine
COMT- catechol-O-methyltransferase
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S-Methylation of 6-Mercaptopurine
TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent
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GLUTATHIONE CONJUGATION
Glutathione
-glutamyl-cysteinyl-glycine
Active site of a GST:Nucleophile
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DRUG INTERACTION WITH GLUTATHIONE
mercapturate metabolite of drug
(S-substituted glutathione conjugate)
Glutathione-S-transferase
glutamyl transpeptidase-ץ
Cysteine-glycine conjugateCysteinyl glycinase
Cysteine conjugateN-acetylase
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MERCAPTURIC ACID FORMATION
• Conjugation of substrate to glutathione by the enzyme glutathione transferase
• Hydrolytic removal of glutamic acid by glutamyl transpeptidase
• Hydrolytic removal of glycine by cysteinyl glycinase• Acetylation of the cysteinyl substrate by
N-acetyltransferase to form the N-acetylated cysteinyl conjugate of substrate; substrate referred to as a “mercapturate”
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METABOLISM OF NAPHTHALENE BY GLUTATHIONE CONJUGATION
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TRANSULFURATION
Inactive
Mediated bymercaptopyruvate sulfurtransferase
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Q & AQ & A
Those are my thoughts.Those are my thoughts.– What are yours?What are yours?
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THANK YOU