Metabolism
Metabolism
Metabolism
Mahwish Akhtar
Ph.D. (Pharm. Chem.)
Assistant Professor
DCOP, DUHS
MEDICINAL CHEMISTRY I
617
Lecture 16-18
4th year, 7th semester
OBJECTIVES
• At the end of the lecture student will be able to
define
– Biotransformation
– Phases of drug metabolism
– Phase I
– Phase II
DRUG BIOTRANSFORMATION
DRUG BIOTRANSFORMATION
• The metabolism of a drug or toxin in a body is an
example of biotransformation.
• The body typically deals with a foreign compound
by making it more water-soluble, to increase the
rate of its excretion through the urine.
• There are many different process that can occur;
the pathways of drug metabolism can be divided
into:
• phase І
• phase II
DRUG BIOTRANSFORMATION
• Drugs can undergo one of four potential bio-
transformations:
– Active Drug to Inactive Metabolite
• Lidocaine, Nitroglycerin
– Active Drug to Active Metabolite
• Codeine --- morphine
• Tramadol --- O-desmethyltramadol
DRUG BIOTRANSFORMATION
• Drugs can undergo one of four potential bio-
transformations:
– Inactive Drug to Active Metabolite
• Lisdexamphetamine
• Prodrug of Epinephrine: Dipivefrin
– Active Drug to Toxic Metabolite (bio-toxification)
– Conversion of secondary amines in the stomach into
carcinogenic nitrosamines via NO pathway.
– Nicotine into the nitrosated carcinogenic NNK (4-(methylnitrosamino)- 1-(3-
pyridyl)-1-butanone) in the lung.
– Hypoglycin A into the highly toxic MCPA-CoA
Metabolite Examples and notes
activity
Inactive Routes that result in the formation of inactive metabolites are often referred to as
(detoxification) detoxification.
Similar The metabolite may exhibit either a different potency or duration of action or both to the
activity to the original drug.
drug
Different
activity
Toxic
metabolites
DRUG BIOTRANSFORMATION
• Phase I
• Includes oxidative, reductive, and hydrolytic reactions.
• In these type of reactions, a polar group is either
introduced or unmasked, so the drug molecule
becomes more water-soluble and can be excreted.
• Reactions are non-synthetic in nature and in general
produce a more water-soluble and more-active
metabolites.
• The majority of metabolites are generated by a
common hydroxylating enzyme system known
as Cytochrome P450.
DRUG BIOTRANSFORMATION
• Phase II reaction
• These reactions involve covalent attachment
of small polar endogenous molecule such as
glucuronic acid, sulfate, or glycine to form
water-soluble compounds.
• This is also known as a conjugation reaction.
• The final compounds have a larger molecular
weight.
DRUG BIOTRANSFORMATION
Metabolism
Metabolism
DRUG BIOTRANSFORMATION
Olefins
• Oxidation
– Oxidation of aromatic moieties (aromatic hydroxylation)
• Arenes to arenols
1. Propranolol
2. Phenobarbital
3. Phenytoin
4. Phenylbutazone
5. Atrorvastatin
6. 17α-Eyhinylestradol
7. Warfarin
8. Amphetamine
OXIDATION
Amphetamin
Phenytoi p- e
n hydroxyphenytoin
Warfarin sodium
17-α-Ethinylestradiol Propranolo
l
Phenylbutazon
e
Atorvastati
OXIDATION
OXIDATION (Aromatic hydroxylation)
• Oxidation of olefins
OXIDATION
• Oxidation of olefins
OXIDATION
• Oxidation of olefins
– 7, 12-dimethylbenz [a] anthracene
– carbamazepine
OXIDATION
• Oxidation of olefins
– 7, 12-dimethylbenz [a] anthracene
– carbamazepine
OXIDATION
Pentazocine
BENZYLIC CARBON
Tolbutamide Metabolism
Dicarboxylic acid is
the major metabolite
Tolmetin sodium
Hydroxylation at C α to C=O and C=N
The benzodiazepines
are classic examples
with both functionalities
Pentobarbital
Metabolism
Ibuprofen
+
Metabolism
Alicyclic (nonaromatic
ring) Hydroxylation
Acetohexamide Metabolism
Oxidation Involving Carbon-
Heteroatom Systems
■ C-N, C-O and occasionally C-S
■ Two basic types of biotransformation processes:
1. Hydroxylation of α-C attached directly to the heteroatom (N,O,S).
The resulting intermediate is often unstable and decomposes
with the cleavage of the C-X bond:
■ Deamination and N-dealkylation differ only in the point of reference; If the drug is R1 or R2
then it is a deamination reaction and If the drug is R3 or R4 then it is an N-dealkylation
N-Dealkylation (Deamination)
■ In general, least sterically hindered carbon (α) will be hydroxylated first, then the next, etc.
Thus the more substituent on this C, the slower it proceeds; branching on the adjacent
carbon slows it down, i.e. R1 , R 2 = H is fastest.
■ Any group containing an α-H may be removed, e.g., allyl, benzyl. Quaternary carbon
cannot be removed as contain no α-H
■ The more substituents placed on the nitrogen the slower it proceeds (steric hindrance)
■ The larger the substituents are the slower it proceeds (e.g. methyl vs. ethyl). In general,
small alkyl groups like Me, Et and i–Pro are rapidly removed; branching on these
substituents slows it down even more
Imipramine N-
Dealkylation
3 oAmine drugs
1°
amines
2°
amines
3°
amines
■ The attack is on the unbonded electrons so 3o amines can be oxidized
■ Generally, only occurs if nothing else can happen, so it is a rare reaction
■ Performed by both amine oxidases and hepatic MFO’s (mix function
oxidase)
■ Good examples would include amines attached to quaternary carbons
since they cannot be deaminated
Chlorphentermine N-
Hydroxylation Hydroxylamin
e
Nitros
o
Nitr
o
Phentermin
Amantadin
e
e
Amide
s
Trimethoprim O-Dealkylation
Codein Phenaceti Indomethaci
e n n
Metoprolo
Prazosi l
n
■ One exception that appears to be a form of O-dealkylation is the
oxidation of ethanol by CYP2E1
■ In this case R3 is hydrogen instead of carbon to form the terminal
alcohol rather than an ether
■ The enzyme involved is CYP2E1 and has been historically referred
to as the Microsomal Ethanol Oxidizing System (MEOS)
Oxidation involving C-S System
■ S-
Dealkylation
Steric hindrance discussion similar to N-
dealkylation
■ Desulfuration
■ S-Oxidation
Oxidative
Dehalogenation
• Reduction
• Aldehyde to alcohol
• chlorpheniramine to
aldehyde metabolite
to reduce alcohol and
oxidize to carboxylic
acid
REDUCTION
• Reduction
• Ketone to 2˚ alcohol
(acetophenone)
REDUCTION
• Reduction
• Nitro group (clonazepam) to amine
ce
HYDROLYSIS
• Hydrolysis
HYDROLYSIS
• Hydrolysis (aspirin)
= +
Phase II
Phase II Metabolism
• Phase II is usually the true detoxification of
drugs
• Occurs mostly in cytosol
• Gives products that are generally water
soluble and easily excreted
• Includes sugar conjugation, sulfation,
methylation, acetylation, amino acid
conjugation, glutathione conjugation
Phase II Metabolism
• Transferase: is any one of a class of
enzymes that enact the transfer of specific
functional groups
• Cofactor: a substance (other than the
substrate) whose presence is essential for
the activity of an enzyme.
Phase II Metabolism
Conjugation (Phase 2)
Glucuronic acid Conjugation
Sulphate Conjugation
Glutathione Conjugation
Acetyl Conjugation
(Acetylation)
Glutathione Conjugation
3'-Phosphoadenosine-5‘-phosphosulfate (PAPS)
-OH, -COOH, -NH2 , -NR2 , -SH, -CH
UDP-glucoronosyl- transferase
GLUCURONIDATION
Glucuronidation
SULFATION
Sulfation
(PAPS, 3’-phosphoadenosine-
5’-phosphosulfate)
GLUTATHIONE CONJUGATION
Glutathione Conjugation
ACETYLATION
Acetylation
METHYLATION
Methylation
• Addition of methy group
• Cofactor is catechol-O-methyltransferase
(COMT)
Methylation
-COOH
Glycine or Glutamine N- acyltransferase
GLYCINE/GLUTAMINE
GLYCINE/GLUTAMINE
• Glutamine
GLYCINE/GLUTAMINE
Glycine Conjugation
Factors affecting Drug
Metabolism
Factors affecting Drug Metabolism
• Disease Factors
• Liver Disease- cirrhosis, alcoholic liver disease, jaundice, carcinoma
• Major location of drug metabolizing enzymes
• Dysfunction can lead to impaired drug metabolism decreased
enzyme activity
• First pass metabolism effected-may increase 2-4 times
bioavailability
• Result in exaggerated pharmacological responses and adverse
effects
• Cardiac failure causes decreased blood flow to liver
• Hormonal diseases, infections and inflammation can change drug
metabolizing capacity
Factors affecting Drug Metabolism
• Age
• Newborns and infants- metabolize drugs
relatively efficiently but at a rate generally
slower than adults
• Full maturity appears in second decade of life
• Slow decline in function associated with aging
Factors affecting Drug Metabolism
• Genetic Variation
• Wide variability in response to drugs b/w individuals
• Consequences of such variation may be therapeutic failure or an adverse
drug reaction
• Genetic diversity is rule rather than the exception with all proteins,
including drug metabolizing enzymes
• Allelic variants with different catalytic activities from that of the wild-type
form have been identified
• Inheritance leads to subpopulations (genetic polymorphisms) with
different drug metabolizing abilities
– Lack of activity
– Reduction in catalytic ability
– Enhanced activity
• Frequency of polymorphism often varies according to ethnic ancestry of
individual
Genetic factor
Factors affecting Drug Metabolism
• Gender
• Responsiveness to certain drugs is different
for men and women
• Pregnancy-induction of certain drug
metabolizing enzymes occurs in second and
third trimester
• Hormonal changes during development have
a profound effect on drugs metabolism
SAR &QSAR
SAR &QSAR
HANSCH ANALYSIS
• Electronic properties
• Lipophilicity
• Steric effect
FREE-WILSON ANALYSIS
• Substitution at specific position
MIXED APPROACH
• Follow above rules
REFERENCES
• Foye’s the Principles of Medicinal Chemistry, 6th ed,
Lippincott William & Wilkins
• Textbook of medicinal chemistry, Vol 1, by V.
Alagarsamy, Elsevier.