Pathways of drug

biotransformation

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 Presented To:
Sir Mohsin
Presented By:
Amina Muzaffar (17305)
ShaistaGul (17303)
JaveriaAjaz (16234)
TehreemAnwar (17293)
Kainat Nadeem (17335)

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AMINA MUZAFFAR
17305

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 The biochemical alteration of drug or
xenobiotic in the presence of various
enzymes that acts as a catalyst which
themselves not consumed in the
INTRODUCTION reaction and there by may activate or
deactivate the drug is called
biotransformation.

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 Phase 1: Biotransformation

Attachment of new functional groups, transformation of exist. funct.

groups

Phases of oxidation, reduction, hydroxylation, hydrolysis etc.

Biotransfor- Phase 2: Conjugation

mation
Masking of an exist. funct. group by for instance

acetylation, glycosylation, attachment amino acid etc

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 Phase-1
Metabolism by cytochrome P450 enzyme system
(CYP450)
Located in endoplasmic reticulum (liver and other cells)
Electron transport system - oxidation, monooxygenase
Heme protein + flavoprotein
Capable of oxidation - many different xenobiotics
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Phase-1
OXIDATION REDUCTION HYDROLYSIS

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 substrate loses
electrons

Oxidation  addition of oxygen,

dehydrogenation,
simply transfer of
electrons

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  alcohol dehydrogenation
 aldehyde dehydrogenation
 alkyl/acyclic hydroxylation
 aromatic hydroxylation
Common  deamination
examples of  desulfuration
oxidation.  N-dealkylation
 N-hydroxylation
 N-oxidation
 O-dealkylation
 sulphoxidation
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 I) Aromatic hydroxylation
Phenylbutazone to Oxyphenbutazone
II) Side chain hydroxylation
Oxidation Pentobarbital to Hydroxy-pentobarbital
De-Alkylation Reactions
III) O-dealkylation
Codeine to Morphine

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SHAISTA GUL
17303

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IV) N-dealkylation
Imipramine to Desipramine
V) S-dealkylation
6-methylthiopurine to 6-
Mercaptopurine

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VI) Deamination
Amphetamine to Phenylacetone
VII) Sulfoxidation
Chlorpromazine to chlorpromazine
sulfoxide
VIII) N-oxidation
Trimethylamine to trimethylamine
oxide
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 Substrate gains electrons
Reduction Occurs when oxygen content
is low

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 I) Azoreduction
Reduction Sulfasalazine to Sulfapyridine
+ 5-Aminosalicylic acid

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II) Nitroreduction
Chloramphenicol to Arylamine
(AminoChloramphenicol)
III) Alcohol dehydrogenase
Trichloroacetaldehyde to 2,2,2-
Trichloroethanol

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 Addition of water splits the
molecule into
two fragments or smaller molecules
Hydrolysis  -OH gp to one fragment and –H to
other
 Eg : Larger chemicals such as
esters, amines, hydrazines, and
carbamates
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 I) Ester hydrolysis
Procaine to p-aminobenzoic
acid +
Hydrolysis N,Ndiethylaminoethanol
II) Amide hydrolysis
Phthalylsulfathiazole to
Sulfathiazole + phthalic acid
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KAINAT NADEEM
17335

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 Conjugation
These reactions require binding
of a high energy molecule and an
Phase-2 enzyme called as conjugating
agent
more water-soluble product
formed

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 • Conjugating reagents
Kinetics of • Kinetics of conjugating reactions
conjugation a. high capacity e.g. glucuronidation
b. low capacity conjugation e.g.
glycine

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High capacity conjugation reactions
Zero order kinetics(at high doses)
1st order(normal doses)
Nonlinear kinetics(at high drug concentration)
Example:
 Glucuronidation
Low capacity conjugation reactions
Nonlinear kinetics(at normal therapeutic
concentration)
Example:
 Glycine, sulfate, glutathione conjugation
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CONJUGATION REACTION CONJUGATING AGENT HIGH-ENERGY INTERMEDIATE

Glucronidation Glucronic acid Uridine diphophoglucronic

acid(UDPGA)

Sulphate conjugation Sulphate 3’-phosphoadenosine-5-

phosphosulphate(PAPS)

Amino acid Glycine Coenzyme A thioesters

conjugation(hiopporates)

Acetylation Acetyl CoA Acetyl CoA

Methylation CH3 from SAM S-adenosylmethionine

Glutathione Glutathione Arene oxides,epoxides

conjugation(mercapturine acid
conjugation)
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25
TEHREEM ANWAR
17293

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Glucuronic Acid
Conjugation

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  Main Pathway of Phase II conjugation reactions. Takes
place in liver.
 Results in formation of glucuronides
 These conjugates follow biliary excretion.
 Substances metabolized by this pathway include drugs, ,
Glucuronic
bilirubin, androgens, estrogens, mineralocorticoids,
Acid
glucocorticoids, fatty acid derivatives and bile acids.
Conjugation
 Properties of the substances that follow this pathway
include:
1.Increase Molecular weight
2. Increase polarity
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Sulphate Conjugation

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 • Very Common
• Water Soluble Metabolites
• Common pathway for metabolism of “hydroxy
Sulfate
Conjugation
Compounds” such as
a. Steroids
b. Isoprenaline
c. Chlorpromazine
d. Salicylamide
• They undergo sulphate conjugation in intestine
resulting in their inactivity
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Amino-Acid
Conjugation

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• Conjugating agents include both Glycine ( Mammals)
and Glutamine ( in lower invertebrates)
• Aromatic acids usually are conjugated with glycine.
• Carboxylic acid is activated in combining with ATP to
form Co-enzyme A derivative before conjugation
with glycine (reaction is catalyzed by amino acid acyl
transferase enzyme)
For Example
• Salicylic Acid
• Benzoic Acid
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Methyl Conjugation

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 • Leads to less water soluble form and are
excreted slowly
• Two types
i. N-Methylation
Methyl
Nor-adrenaline to Adrenaline
Conjugation
ii. S-Methylation
Dimercaprol (War Gas)

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Javeria Ajaz
16234

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 • Amine compounds are metabolized into
acetyl derivative by enzymes acetyl CoA or
Acetyl Transferases
Acetyl
• Acetyl reactions are less desirable
Conjugation
• Less polar and less water soluble
conjugates are formed

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Drugs undergoing this
process include sulfonamides,
isoniazid, dapsone,
hydralazine, procainamide

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Acetylated product is usually less
polar than parent drug
 Long elimination half life
Generic polymorphism of N-
ACETLY TRANFERASE
1. Fast acetylators
2. Slow acetylators

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Glutathione and
mercapturic acid
conjugation

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Glutathione (GSH) is tripeptide of the three amino
acids glutamate, cysteine and glycine

Drugs that have active nitro and halogen group

undergo glutathione conjugation
Glutathione is important in detoxification of
reactive oxygen intermediate into non-reactive
metabolites and in the main intracellular molecule
for protection of the cell against reactive
electrophilic compound.

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42
Paracetamol

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Questions.

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• What are names of phase I reaction?
• Why there is need of phase II reaction?
• Name of class in which amine group is attached
with aromatic group?
• What is meaning of being a slow acetylator?
• Describe the pathways by which paracetamol is
metabolized?
• What harm can acetylation of sulfonamides do?
How can we overcome them?
• What is the effect of slow acetylators on isoniazid ?
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 1. Applied Biopharmaceutics
References & Pharmacokinetics, 7e Leon
Shargel, Andrew B.C. Yu

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JAZAKALLAH AL-
KHAIR

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