drug metabolism ok
TRANSCRIPT
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Drug MetabolismChapter No 5
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Metabolism means Catabolism (breaking
down of substances)
Anabolism (building up or synthesis of
substances)
But when we speak about drug metabolism, it isonly catabolism
That is drug metabolism is the break down of drug
molecules
So what is building the drug molecules? We use
the word synthesis, then
Drugs are synthesized in laboratory and thus is not
an endogenous event
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Drug metabolism (biotransformation)It is the type of chemical reactions which
leads to modification of drugs
Drugs are converted from one form to an other tomake them more active ,less active and finallyinactive and to leave the body.
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How Do Drugs Work?
Drugs are distributed throughout the body by the blood
and other fluids of distribution. Once they arrive at the
proper site of action, they act by binding to receptors,
usually located on the outer membrane of cells, or on
enzymes located within the cell.
Usually results in loss of pharmacological activity
Sometimes may be equally or more active than parent
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Phase I reactions:Hydroxylation
oxidation
Reduction
Hydrolysis
Phase II reactions: glucuronidiationSulfation
Acetylation
Methylation
Pathways of drug
metabolism
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PHASE I AND PHASE II REACTIONS
IN DRUG METABOLOISN
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Convert the parent drug to a more polar (water-
soluble) and/ or more reactive product by
unmasking or inserting a polar group such as-OH, -SH, -NH2
PHASE I REACTIONS
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PHASE II REACTIONS
increase water solubility by conjugation of the
drug molecule with a polar moiety such as
glucuronate, sulfate, acete, glutathione and
methyl groups
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Both types of reaction convert
relatively lipid-soluble original
drug molecules into more water-
soluble metabolites that are
more easily excreted
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Aromatic Hydroxylation
To answer this question we need to examine the
structure ofdiazepam .
It is extremely important to remember that chemical
structure is intimately linked to reactivity.
PHASE I REACTIONS
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N
N
O
Ph
Cl
CH3
N
N
O
Ph
Cl
CH3
OH
N
HN
O
Ph
Cl
Diazepam(Sustained anxiolytic action)
Hydroxylation
Temazepam(Short duration)
Oxazepam(short duration)
N-Demethylation OH
The metabolite may exhibit either a different potency orduration of action or both to the original drug.
R C C R'
O H
H
R C C R'
O H
OH
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R1 C R2
S
R1 C R2
O
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R1 S R2 R1 S R2
O
R1 S R2
O
O
Sulfoxide Sulfone
S-Oxidation (Drugs containing)
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Reductive Reactions
Reductive Reactions
Bio reduction of C=O (aldehyde and keton) generates alcohol
(aldehyde 1o alcohol; ketone 2o alcohol)
Nitro and azo reductions lead to amino derivatives
Reductive cleavage of disulfide (-S-S-) linkages and reduction ofC=C are minor pathways in drug metabolism
Reductive dehalogenation is a minor reaction primarily differ from
oxidative dehalogenation is that the adjacent carbon does not
have to have a replaceable hydrogen and generally removes one
halogen from a group.
(Then All products converted into glucuronidated, carboxylic acid
etc become water soluble compounds)
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R C N
H
H
R C N
H
H
H
H
H
OH
R C N
H
H
R C N
H
H
O
O
1 amineHydroxylamineNitrosoNitro
O
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N N R2R1 R1 NH2 H2N R2+
Azo Two 1 amines
HNR1
Hydrazo
HN R2
N NR
Azido
NH2R
Amine
NH + N N
N2
Reduction of Nitro & Azo Compounds
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The cytochrome P450 is a large and diverse group ofenzymes that catalyze the oxidation of organic substances
The most common reaction catalyzed by cytochromes P450 is
a monooxygenase reaction, e.g., insertion of one atom of
oxygen into an organic substrate (RH) while the other oxygenatom is reduced to
P450 and its Function in Drug Metabolism
N
N
H
H
O
O
O
N
N
H
H
O
O
OOH
CYP450
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R1 R1
OH
R1
O
R1
OH
OH
R1
SGlutathione
R1
Macromolecule
Spontaneous
Epoxide hydrolase
Glutathione
Macromolecule
R1
OH
OH
Aromatase
CYP450
OH
OH
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O
O
O
NH2
NH2
N
N
CH3
H3C
H3C
O
O
O
NH2
NH2
N
N
CH2
H3C
H3C
OH
O
O
NH2
NH2
N
NH3C
H3C
OH
Sponta
neousCY
P450
Oxidation involving C-O System (O-Dealkylation)
Trimethoprim O-Dealkylation
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R C
H
Cl
Cl
R C
OH
Cl
Cl
R C
O
Cl
R C
O
OH+
H Cl
+H2O
CYP450
H Cl
+
Spontaneous
Oxidative Dehalogenation
Make the drug more polar more water soluble. (oxidation,reduction, hydrolysis)
Oxidation reaction:introduces functional group (OH,NH2,SH)
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Reduction Reactions:
nitrobenzene anilineNO2 NH2
Chloral hydrate trichloroethanol
Hydrolysis:
Ester-C-O and amides-C-NAcetylcholine choline +acetate(ester)Procainamide (lidocaine) (amide)
H3C O
O
O
OH
H3C OOH
O
OH
OH
+
Aspirin Salicylic Acid
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CH3
CH3N
H2N
O
O
CH3
CH3N
H2N
O
H
N
Procainamide
Procaine
H2N
O
OH
Slow Hydrolysis
Rapid Hydrolysis
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Metabolic Oxidation of Alkene
EpoxideAlkene trans dihydrodiol derivative
Epoxide hydrolaseOOHOH
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Oxidation by soluble enzyme in cytosol or mitochondria
of cellse.g
1. dehydrogenases and oxidases
Ethanol acetaldehyde acetic acid.
Methanol formaldehyde formic acid
CH3CH2OH CH3CHOCH3COOH
2. monoamide oxidase(noradrenaline)
3. Hypoxanthine xanthine uric acid
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Characteristics of Phase I Products(Result of DrugMetabolism)
1. Inactivation (abolish the activity)Oxidation of Phenobarbital and alcohol
Hydrolysis of acetylcholine
2. Conversion of active drug to another active one.Diazepam oxydiazepam
Codeine , heroin Morphine
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3. Conversion of drug to toxic metabolites:Paracetamol acetaminopen (hepatic toxicity)
Halothane metabolite hepatotoxicity
4. Activation of pro-drugChloral hydrate trichloroethanol
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Phase-II Metabolism
It involves union of the drug with one of several
polar(water soluble ) endogenous molecules that
are product of intermediatory metabolism toform water soluble conjugate which is readily
eliminated by the kidney or if the molecular
weight is more than 300 in the bile
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Subsequent reaction in which a covalent linkage
is formed between a functional group on the
parent compound or Phase I metabolite and an
endogenous substrate such as glucuronic acid,
sulfate, acetate, or an amino acid
Highly polar rapidly excreted in urine and feces
Usually inactive - notable exception is morphine
6-glucuronide
Phase II Conjugation Reaction
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Factors affecting drug metabolism
Age: In elderly metabolism is reduced because liver mass , andliver blood flow are decreased
Pregnancy: Hepatic metabolism is increased
Disease: Acute inflammatory disease of liver (viral ,alcoholic) Food: some specific dietary factors induce drug metabolizing
enzymes
e.g. alcohol, charcoal grilled beef, cabbage.
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Pregnancy: Hepatic metabolism is increased
This leads to increased clearance of drugs such as phenytoin
and theophylline
Disease: Acute inflammatory disease of liver (viral ,alcoholic)and cirrhosis affect function of hepatocytes and blood flow
through the liver, this results in increased systemic availability
of drugs .
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SUMMARY OF DRUG METABOLISM
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General Metabolic Pathways
Glucuronic acid conjugation
Sulfate Conjugation
Glutathion or mercapturic acid
Acetylation
Methylation
Reduction
Aldehydes and ketones
Nitro and azo
Miscellaneous
Oxidation
Aromatic moieties Olefins
Benzylic & allylic C atoms
and a-C of C=O and C=N
At aliphatic and alicyclic C
C-Heteroatom system
C-N (N-dealkylation, N-oxideformation, N-hydroxylation)
C-O (O-dealkylation)
C-S (S-dealkylation, S-oxidation,
desulfuration)
Oxidation of alcohols and
aldehydes
Miscellaneous
Phase II -Conjugation
Phase I -Functionalization
Drug
Metabolism
Hydrolytic Reactions
Esters and amides
Epoxides and arene oxides
by epoxide hydrase