Metabolism Lecture 6
Dr Maura Grealy
Most drugs:
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Leave the body in the urine:
UNCHANGED
or as Polar metabolites
Some secreted into bile via liver (most
reabsorbed via GIT)
Some faecal elimination (e.g. rifampicin)
Some excretion via lungs (volatile/gaseous
agents)
Some excretion occurs in sweat or milk
(nursing mothers)
Metabolism (Biotransformation)

Can alter a drug in 4 important ways
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Convert an active drug into an inactive drug
Convert an active drug to an active or toxic
metabolite
Convert an inactive prodrug to an active
drug
Convert an unexcretable drug to an
excretable metabolite

Inactive prodrugs have been developed
to
A.
B.
C.
D.
reduce drug toxicity
increase drug half-life
decrease hepatic drug metabolism
increase drug absorption
Lipophilicity

To be excreted by kidneys in urine a
drug needs to be

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Lipophilic drugs


Hydrophilic?
Hydrophobic (lipophilic)?
Not eliminated efficiently by kidney
Biotransformation into less lipophilic
compounds


Polar metabolites
Aids elimination in the kidney
Drug Elimination

Irreversible loss of drug from the body

Main Routes
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Kidneys
Hepatobiliary system
lungs
2 processes
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Metabolism
Excretion
Metabolism
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Primary goal is drug inactivation
Primary site is the liver


Uses enzymes to convert drug from one
form to another (usually less active) form
Enzymes = cytochrome P450 system



Large group of related enzymes in the liver
Main job is detoxifying foreign chemicals
including drugs
Divided into
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
Phase I reactions
Phase II reactions
Chemical reactions in drug metabolism


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Oxidation
Reduction
Hydrolysis
Conjugation

Result in the formation of polar metabolites
both less active than, and more readily
excreted than, the parent compound
2 phases of drug metabolism

Phase 1 – usually precedes phase 2
(“Functionalisation”)


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Oxidation
Reduction
Hydrolysis
CATABOLIC

Products often more
chemically reactive
(paradoxically sometimes more
toxic or carcinogenic than the
parent drug)
Hydrolysis
Phase 2 of drug metabolism

Biosynthetic

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ANABOLIC
Conjugation


(allows attachment
of a group)
Usually results in
inactive products
Site of drug metabolism

Liver


Epithelial cells of small intestine


High concentrations of many drug
metabolizing enzymes
Expression of certain isoforms
Kidney, Lung, Skin also
Liver enzymes

Embedded in smooth endoplasmic
reticulum

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Microsomal enzymes (because ER breaks
into small fragments called microsomes on
homogenisation and centrifugation)
Drug must cross plasma membrane to get
there

Thus more NB for lipophilic drugs
Phase I Reactions

Cytochrome P450 enzymes

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Differ from each other
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Haem proteins
Large superfamily of related enzymes
CYP + number
Amino acid sequence
Sensitivity to inhibitors / inducers
Specificity of reactions they catalyse
3 main genes are CYP1, CYP2, CYP3
CYPs CYtochrome P450 Family)

CYP1 Family:


CYP2 Family:
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Primarily metabolize carcinogens, some
drugs as well.
Metabolize many important drugs
CYP3 Family:

Most abundant family in human liver,
metabolize many important drugs
Phase I reactions - Oxidation
Drug + O2 + NADPH + H+
Drug-OH + H2O + NADP+
PHASE 1 Oxidation reactions
Hydroxylation -CH2CH3
-CH2CH2OH
Eg barbiturates, cyclosporine
Oxidation -CH2OH
-CHO
Eg methanol, ethanol
N-de-alkylation -NHCH3
-COOH
-NH2 + CH2O
e.g methamphetamine, lidocaine
Oxidative deamination -CHCH3
-COCH3
+
NH3
|
NH2
e.g histamine, noradrenaline
Phase I in action
Imipramine
N
CH2CH2CH2NCH3CH3
Phase I in action
Imipramine
N
desmethyl
imipramine
(antidepressant)
CH2CH2CH2NCH3CH3
2-hydroxy
imipramine
(cardiotoxic)
Phase I rxns not involving CYP450

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95% of oxidation biotransformations are
via CYP 450
Others
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Alcohol dehydrogenase

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Methanol to formaldehyde (toxic)
Monamine oxidase

Oxidation of catecholamines and tyramine
Reduction (electron gain)

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Addition of H to N, O, or C=
Nitro groups changed to an amine

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Carbonyl groups changed to a hydroxyl

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RNO2
RNH2
eg chloramphenicol
RC=O
RC-OH
eg haloperidol; methadone
Enzymes for Reduction
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Aldo-keto reductase gene superfamily
CYP family can also participate in
reduction reactions
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Eg halothane (anaesthetic)
De-halogenated R-X
R-H
Warfarin by CYP2A6
Hydrolysis
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Drugs containing esters
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RCOOR’
RCOOH +HOR’
Eg procaine, succinylcholine, aspirin
Hydrolysed by non-specific esterases

In liver, plasma, GIT
Hydrolysis
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Amides RCONHR’
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Procainamide, lidocaine
Hydrolysed by amidases
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RCO-OH +H2NR’
In liver
Polypeptide drugs eg insulin, growth hormone

Transformed by peptidases

In plamsa, red blood cells, + many tissues

Hepatic cytochrome P450 drugmetabolizing enzymes are primarily
found in
A.
B.
C.
D.
cell nuclei
plasma membranes
the cytoplasm
the smooth endoplasmic reticulum