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Drug Metabolism
Drug Metabolism
DRUG METABOLISM
controlled reactions.
Consequences of metabolism
Active metabolites
parent drug
It may change the usual activity of the substrate
Toxic metabolites.
1. Genetic varieties
Variations in the genetic codes of individuals can
1. Genetic varieties
These differences in enzyme concentration and
2. Physiological factors
The metabolic differences found within a species are
believed to be due to variations in age, sex, nutritional
status and diet, and diseases
Age.
The ability to metabolize drugs is lower in the very
syndrome
Factors affecting metabolism
2. Physiological factors
Sex.
The metabolic pathway followed by a drug is
2. Physiological factors
Disease states
Diseases that affect the liver will have a large effect
on drug metabolism.
Diseases of organs, such as the kidneys and lungs,
Phase I reactions
This functionalization provide a site for phase II
reaction.
Certain drugs may be eliminated from the body at
Phase II reactions
Also referred to as synthetic or conjugation
reaction
In this phase the metabolites from phase I or a drug
Assignment;
Is metabolism the same as detoxification? 5mks
They involve;
Hydrolysis
Oxidation
Reduction
Dethioacetylation
Isomerization.
Oxidative reactions
Removal of hydrogen
Loss of electrons
Oxidative reactions
Cyp 2D6
Cyp 2C8/9
Cyp 1A1/2
Oxidative reactions
Cyp 3A4/5 (the number 3 stands for the family, A for the
subfamily while 4 and 5 represent individual
isoenzymes).
This accounts for about 40% of all oxidations.
Cyp 2C8/9
Acts on warfarin and phenytoin which have narrow
safety margins.
Cyp 1A1/2
Responsible for activation of several procarcinogens.
Oxidative reactions
iii. N- dealkylation
It involves removal of an alkyl chain attached to the
iii. N- dealkylation
1 – RNH2
0
20 – R-NH-CH
3
Oxidative reactions
amines
The reaction also occurs more readily when the
oxidation reactions.
Oxidative reactions
iii. N- dealkylation
iii. N- dealkylation
Oxidative reactions: iv. Oxidative deamination
secondary amines.
Products are either ketones or aldehydes depending on
urine
Secondary and tertiary amines rarely undergoes this
occurs concurrently.
iv. Oxidative deamination
R is purine molecule.
vii. Sulfoxide formation/sulfoxidation
by this reaction
Catecholamines
adrenaline
noradrenaline
dopamine
NON MICROSOMAL OXIDATIVE
REACTIONS.
NON MICROSOMAL OXIDATIVE
REACTIONS
3.Purine Oxidation
Xanthine oxidase found in the liver cytosol
metabolizes endogenous and exogenous non
methylated or non-alkylated purine to uric acid.
The purines are oxidized from their hypoxanthine to
their xanthine derivatives and finally to uric acid.
The uric acid is eliminated through urine but
sometimes accumulates in joints causing gout.
Reaction can be blocked by xanthine oxidase inhibitors
eg allopurinol, febuxostat
NON MICROSOMAL OXIDATIVE REACTIONS.
NON MICROSOMAL OXIDATIVE REACTIONS.
4. Beta Oxidation
The alkyl chain of alkyl carboxylic acids is oxidized to
an alcohol at the beta position.
NON MICROSOMAL OXIDATIVE REACTIONS.
5. Aromatization reaction
Aliphatic cyclic compounds are converted to
aromatic derivatives. Reaction occurs only in pigs
NON MICROSOMAL OXIDATIVE REACTIONS.
6. Oxidative dehalogenation
It affects halogen containing compounds like
insects.
It involves removal of halogen from a compound.
i. Nitro reductions
The reaction does not occur in developed (especially
in man) unlike in less developed organisms like
bacteria.
The primary amine can undergo further phase I or II
reactions.
1. MICROSOMAL REDUCTION
REACTIONS
E.g. Chloramphenicol
1. MICROSOMAL REDUCTION REACTIONS
2. Azo reduction
Azo reductases convert aromatic azo aromatic
compounds into two amines per compound.
The coenzyme is NADPH. Examples protonsil – is a
sulfanilamide, It undergoes reduction to produce a
sulfanilamide.
The reaction is slow in mammals but fast in bacteria.
1. MICROSOMAL REDUCTION REACTIONS
3. Disulfide reduction
1. MICROSOMAL REDUCTION
REACTIONS
Sulphur – sulphur linkage/bonds undergo reactions
leading to the rapture of the S-S bonds and formation
of two sulfides.
It is a very slow reaction that less reaction in less
developed organisms e.g. bacteria.
2. NON MICROSOMAL REDUCTION
REACTIONS.
Amides
Hydrazines
Carbamates
1. GLUCORONIDE CONJUGATION
Takes place in microsomal fraction.
Enzymes involved are known as glucoronyl
transferase.
It occurs in the liver but also to a small extent in the
kidney, intestinal tract, skin and lung.
PHASE II REACTIONS
1. GLUCORONIDE CONJUGATION
Takes place in two stages:
a) Involves formation of the activated form of
glucoronic acid called uridine disphosphate
glucoronic acid (UDPGA) from D glucose – 1 –
phosphate.
b) The UDPGA combines with an active hydrogen from
an acid, OH, phenol, SH, NH2 in the presence of
UDP glycoronly transferase.
PHASE II REACTIONS : GLUCORONIDE
CONJUGATION
2. SULPHATE CONJUGATION
Enzymes involved are sulphate transferases/sulfokinases
found in the cytosol i.e. soluble fraction.
The drugs that can be conjugated through this process
include OHs, phenols and NH2. The activated
transferring molecule phosphoadenosine – 5 –
phosposulphate (PAPS) is synthesized from adenosine –
5 - phosphosulphate (APS).
PHASE II REACTIONS
2. SULPHATE CONJUGATION
PHASE II REACTIONS
3. ACETYLATION
The acetyl group from acetylation is derived from the
acetyl COA, the conjugation is catalyzed by acetyl
transferases found in the cytosol/soluble fraction.
Hydrozines and primary aromatic amines, OH and SH
may undergo acetylation. i.e
PHASE II REACTIONS: 3. ACETYLATION
PHASE II REACTIONS: 3. ACETYLATION
acetylators.
The slow acetylators are prone to toxicity where drugs
that are metabolized primarily through acetylation
slow acetylators are more likely to have PN with
isoniazid use.
Acetylated form has low soluble and may accumulate in
5. GLUTATHIONE CONJUGATION /
MERCAPTOPURIC ACID FORMATION
Aromatic hydrocarbons and halogenated aromatic
hydrocarbons undergo glutathione conjugation.
Glutathione is a tri-peptide consisting of cysteine,
glutamic acid and glycine and conjugates with the
substrates via the mercapturic (-SH) function of cysteine.
The enzyme involved is glutathione S-transferase and the
products are mercaturic acid derivatives.
PHASE II REACTIONS
5. GLUTATHIONE CONJUGATION /
MERCAPTOPURIC ACID FORMATION
PHASE II REACTIONS
For ampicillin R1 – H
For Bacampicillin R1 –
For Pivampicilin R1
PRO-DRUGS
a) It should be inactive.
b) Non toxic
c) Easily converted to the parent compound in vivo
d) Should be easily synthesized.
e) Once the pro-drug moiety is removed, the moiety
should be inactive i.e. it should be eliminated without
causing any effect. It thus should be inactive, non-
toxic and readily eliminated.
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