Metabolic changes of drugs and

related organic compounds

Prepared by: Guada Marie O. Ruiz, RPh, DHA-RPh
Introduction to Pharmacy and Chemistry
of medicinals
It is the practice of medicinal chemistry
that is devoted to the discovery and
development of new drugs.

Physicochemical properties of a drug that

affects its biological action.
ORGANIC MEDICINAL CHEMISTRY
• deals with the physicochemical properties of drugs that affect its
biological action

• the practice of medicinal chemistry is devoted to the discovery and

development of new drugs
Drug
• an agent intended
for use in the
diagnosis,
mitigation,
treatment, cure or
prevention of
disease in humans
or in other animals
 PRODRUG
An inactive form of the
drug which needs
conversion in the body to
one or more of its active
metabolites, which is the
active form, and is
capable of producing its
desired pharmacological
action.
Examples:
Levodopa – Dopamine (active form)
Prednisone – Prednisolone (active form)
Receptor
• It is a substance to
which a drug needs to
interact with to
elicit a
pharmacological
response

• induce or inhibit
AFFINITY
• It is the ability
of a drug to bind
to the receptor.
Intrinsic activity
• It is the ability of a drug to
exert a pharmacologic action.
BIOAVAILABILITY

is the fraction of administered drug

that reaches the systemic circulation
in a chemically unchanged form
4 FUNDAMENTAL PATHWAYS

1.ABSORPTION
2.DISTRIBUTION
3.METABOLISM
4.EXCRETION
ABSORPTION:
the transfer of a drug from its
site of administration to the
systemic circulation
DISTRIBUTION
the process by which a drug
reversibly leaves the blood stream
and enters the interstitium
(extracellular fluid) and or the
cells of the tissue
 3. Metabolism
Plays a central
role in the
elimination of
drugs and other
foreign compounds
(xenobiotics)
from the body.
4. EXCRETION
the removal of
metabolic waste
products from the body
by the lungs, kidneys
and skin.
 Lesson 1:
Metabolic Changes of
Drugs and Related
Organic Compounds
DRUG METABOLISM

Biochemical modification of one chemical

form to another, occurring usually through
specialized enzymatic systems.
 Hydrophilic – water loving
GOAL…. Hydrophobic – Water hating
Lipophilic – Lipid loving
Lipophobic – Lipid hating

Polar
Hydrophilic
Water loving
Lipid insoluble
Goal...
Convert lipophilic drugs to hydrophillic
polar substance for excretion
FIRST PASS
EFFECT
Drugs may be
metabolized by hepatic
enzymes to inactive
chemicals.
BIOTRANSFORMATION
• Alteration of a drug
within a living
organism
• Alteration of a drug
molecule in the body
Make the drug water soluble,
polar, hydrophillic for
excretion
Sites of
biotransformation
Most important
organ in
metabolism
others...
• kidneys
• muscle tissue
• lungs
• skin
• blood
General Pathways of
Drug metabolism
 Oxidative rxn

Functionalization Reductive rxn

Pathways

Hydrolytic rxn
Glutathione or
Glucuronic Acid
Mercapturic Acid
Conjugation Conjugation

Conjugation Sulfate
Acetylation
reactions Conjugation
Conjugation with Glycine, Glutamine
and other Amino Acids Methylation
 Oxidative rxn

Functionalization Reductive rxn aka: NON-

SYNTHETIC
Pathways

Carried out usually by REACTIONS

CYP450 Hydrolytic rxn
A polar group is
Glutathione or
either introduced or Glucuronic Acid
unmasked Mercapturic Acid
Conjugation Conjugation

Conjugation Sulfate
Acetylation
reactions Conjugation
Conjugation with Glycine, Glutamine
and other Amino Acids Methylation
 • Introduce a functional polar group
in the xenobiotic

• To make a WATER SOLUBLE COMPOUND

1. Oxidation
• the most common and important in drug
metabolism.
• A direct insertion of a hydroxyl functional
group into the drug molecule
• Mediated via endoplasmic reticulum, mostly by
cytochrome P450 liver enzymes
Oxidation
• Important drugs undergoing metabolism by this
reaction include
1. acetanilide (analgesic)
2. phenylbutazone (analgesic)
3. valproic acid (antiepileptic)
4. carbamazepine (antiepileptic)
5. minoxidil (antihypertensive)
Role of CYP450 Monooxygenases in oxidative
biotransformation
2. Reduction
• Metabolism of many compounds containing carbonyl, nitro
and azo groups.

• Bioreduction of carbonyl compounds generates alcohol

derivatives, whereas nitro and azo reductions leads to amino
derivatives.
2. Reduction
3. Hydrolysis
3. Hydrolysis
• Hydrolysis is major biotransformation pathway for drugs
containing an ester functionality.
• Performed by hydrolytic enzymes called plasma esterases
• Ex. Plasma cholinesterase
Phase II Reaction
 Oxidative rxn

Functionalization Reductive rxn

Pathways

Hydrolytic rxn
Glutathione or
Glucuronic Acid
Mercapturic Acid
Conjugation Conjugation

Conjugation Sulfate
Acetylation
reactions Conjugation
Conjugation with Glycine, Glutamine
and other Amino Acids Methylation
form water-soluble, readily excretable,
inactive and nontoxic conjugated
products

Drug detoxification
pathway
1. Glucuronidation
• It is the most common conjugative pathway in drug
metabolism.

• Drugs that undergo glucoronidation:

Morphine
Acetaminophen
Chloramphenicol
• GLUCORONIDES are highly hydrophilic and water
soluble

• Neonates have undeveloped liver UDP glucoronyltransferase

activity and may exhibit metabolic problem
Chloramphenicol causes Gray baby’s
syndrome
2. Sulfate conjugation
• Leads to water soluble and inactive metabolites.

• Drugs that undergo sulfate conjugation:

methyldopa, salbutamol and terbutaline
2. Sulfate conjugation
3. Glycine and Glutamine conjugation
• The amino acid glycine and glutamine are used to conjugate
carboxylic acids, particularly aromatic acids and arylalkyl
acids.

• E.g. Conversion of benzoic acid to its glycine conjugate,

hippuric acid
GLYCINE

GLUTAMINE
4. Glutathione or Mercapturic acid
conjugation
• Pathway for detoxifying chemically reactive
electrophilic compounds.

• GSH protects vital cellular constituents against

chemically reactive species by virtue of its
nucleophilic sulfhydryl (SH) group.
GLUTATHIONE
5. Acetylation
• Metabolize primary amino groups:
primary aromatic amines,
sulfonamides, hydrazines,
hydrazides, and primary aliphatic
amines.
• The acetyl group used in N-
acetylation of xenobiotics is
supplied by acetyl-CoA.
• Drugs metabolize by acetylation:
Hydralazine (SLE Systemic lupus
erythematosus ),
Isoniazid (peripheral neuropathy)

My Hypotension Lola Nyo

Methyldopa
Hydralazine
Labetalol
Nifidepine
6. Methylation
• Biosynthesis of many endogenous
compounds (e.g. epinephrine and
melatonin)
• Inactivation of numerous
physiologically active amines (e.g.
norepinephrine, dopamine, serotonin
and histamine).
 Enzymatic
Inducers and Inhibitors
Factors affecting DRUG
METABOLISM
FACTOR REACTION
AGE Decreasing of metabolism speed
PREGNANCY Increasing of metabolism speed
GENES Various reactions
LIVER Pathology Decreasing of excretion speed of drugs, depending on their kinetics, type and
stage of liver disease, increasing of bioavailability and decreasing of excretion
speed of orally administered drugs with high hepatic clearance

GI Pathology Changes in metabolism in GI epithelium

NUTRITION Increasing of metabolism speed of certain drugs in case of diet with dominance
of proteins and carbohydrates
Decreasing of metabolism speed in case of heavy digestive disorders linked
with starvation (total or protein)
FACTOR REACTION
ENVIRONMENT Increasing of metabolism speed if in contact with chlorine
insecticides
ALCOHOL Depressing of enzymes that metabolize drugs
-- one time consumption
Induction of enzyme system
-- chronic consumption

SMOKING Increasing of metabolism of certain drugs

Ex. THEOPHYLLINE
WAY OF EXCRETION First-pass effect after peroral administration of drugs
TIME OF INTRODUCTION OF DRUGS Changes in drug metabolism
INTERACTION OF DRUGS Stimulation and depression of enzyme reaction
Factors Affecting Drug Metabolism
• Age differences
• Species and Strain Differences
• Hereditary or Genetic Factors
• Sex Differences
• Enzyme Induction
• Enzyme inhibition
• Pathological conditions
RECALL!
1. An inactive form of the Prodrug
drug which needs
conversion in the body to
one or more of its active
metabolites?

2. What is the most

important organ in
Liver
metabolism?
3. What is the toxic NAPQI
metabolite of
Acetaminophen?

4. What is the drug of NAC

choice for Acetaminophen
toxicity?