Download File

Biotransformation
Siva Nageswararao Mekala
Assistant Professor
Dept. of clinical Pharmacology
Biotransformation
It is the chemical transformation of the
drug within the living organism
What happens to metabolized drug ?
Lipid soluble and Unionized compounds
Converted
Water soluble or more ionized compounds
reducing renal tubular reabsorption

facilitating their excretion
Drug metabolism does not always result in detoxification and
inactivation of drugs
Foreign chemicals or xenobiotics (substances foreign to the
body)
 Environmental contaminants as well as in our diets.
 Plants (phytoallexins) eg, poisonous mushrooms
 Drugs are considered xenobiotics

Most are extensively metabolized in humans.
Humans
exposed
Environmental pollution, food additives, cosmetic products,
agrochemicals, processed foods, and drugs.
( lipophilic chemicals)
If there is absence of metabolism
accumulate in the body,
Resulting in toxicity

Biotransformation reactions may have four different
consequences with respect to pharmacologic activity:
i.
ACTIVATION:
An inactive precursor is converted into pharmacologically
active drug

L-dopa (inactive) to Dopamine(active)
prednisone(inactive) to prednisolone(active)

Such inactive drugs are known as PRODRUGS
Prodrugs have following advantages:




Active form is more stable
Better bioavailability
Desired pharmacokinetics
Less side effects and toxicity
e.g., Enalapril – Enalaprilat
Bacampicillin – Ampicillin
Acyclovir- Acyclovir triphosphate
ii. MAINTENANCE OF ACTIVITY:
An active substance is converted into active metabolite
e.g: Diazepam to Oxazepam
Codeine to Morphine
iii.
INACTIVATION:
An active drug is converted to inactive products
e.g: Pentobarbital to Hydroxypentobarbital
iv. ACTIVE DRUG TO HIGHLY TOXIC METABOLITE :
eg: Paracetamole converts N-acetyl-p-benzoquinoneimine
Sites

Metabolizing enzymes are found in most tissues in the body
with the highest levels located in the tissues of the
gastrointestinal tract [liver, small and large intestines]

For orally administered drug---- LIVER
Lower gut

In addition, drugs may be metabolized by gastric acid (eg, penicillin)

digestive enzymes (eg, polypeptides such as insulin)

enzymes in the wall of the intestine (eg, sympathomimetic catecholamines

Other organs that contain significant xenobioticmetabolizing enzymes include the tissues of the nasal
mucosa and lung

Biotransformation reactions can be assigned to two major
categories:

PHASE - I (NON-SYNTHETIC REACTIONS):
Convertion of the parent drug to a more polar metabolite by
introducing or unmasking a functional group (–OH, –NH2, –SH).

PHASE - II(SYNTHETIC REACTIONS):
Enzymes form conjugate of the substrate
NOTE: Drugs originally containing reactive groups NH2 , OH or
COOH - can undergo direct phase 2 reactions
5/9/2017
PHASE I
In this enzymes carry out
 Oxidation:
Addition of Oxygen and/or removal of Hydrogen . It is the most
important and common metabolic reaction.
 Reduction:
Removal of oxygen or addition of hydrogen
 Hydrolytic reactions:
Breakdown of the compound by addition of water
 Cyclization:
This is formation of ring structure from a straight chain
compound
 Decyclization :
This is opening up of ring structure of the cyclic drug molecule.

OXIDATIVE REACTIONS:
Eg: Phenytoin ,Phenobarbitone ,Propranolol, pentobarbitone

REDUCTION REACTIONS:
Eg: Chloramphenicol , methadone , Halothane ,Warfarin

HYDROLYSIS REACTION:
Eg: Esters: Procaine , Succinylcholine
Amides: lignocaine ,Procainamide


CYCLIZATION: Proguanil
DECYCLIZATION: Barbiturates ,phynytoin
5/9/2017
Classes of enzymes:
i.
Cytochrome P450s (P450 or CYP),
ii Flavin-containing monooxygenases (FMO)
iii Epoxide hydrolases - Hydrolysis of epoxides (mES, sES)
5/9/2017
CYTOCHROME P(CYP)

The CYPs are a superfamily of enzymes, all of which contain a
molecule of heme that is noncovalently bound to the
polypeptide chain

CYPs use O2, plus H+ derived from the NADPH to carry out
the oxidation of substrates
5/9/2017
CYPs
metabolism of dietary and xenobiotic
synthesis of endogenous compounds
CYPs
(> 50)
such as steroids, estrogens
metabolism of bile acids
Specificity
CYP 19
Testosterone
Aromatase (member of the
cytochrome P450 superfamily)
Estrogen(estradiol)
CYP3A4
gene number 4
subfamily A
family 3
www.themegallery.com
CYP 3A4

In humans the 12 CYPs that are important are:
CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6,
2E1, 3A4, and 3A5
CYP1A2, 15%
CYP2A6, 4%
CYP2C9, 20%
CYP2D6, 5%
CYP2E1, 10%
CYP3A4 30%
PHASE II
In Phase II consists of Conjugation reaction.
Phase 2 "transferases“





Sulfotransferases
(SULT)
UDP-glucuronosyl
transferases (UGT)
Glutathione-Stransferases (GST)
N-acetyltransferases
(NAT)
Methyltransferases
(MT)
Addition of sulfate
Addition of glucuronic acid
Addition of glutathione
Addition of acetyl group
Addition of methyl group
PHASE II REACTIONS

Parent drugs or their phase I metabolites undergo coupling or
conjugation reactions with an endogenous substance to yield
drug conjugate

Conjugates are polar molecules that are readily excreted and
often inactive.
5/9/2017
Type of
Conjugation



Endogenous
Reactant
Examples
Glucuronidation
UDP glucuronic acid
(Hydroxyl or carboxyl acid group)
Acetylation
Acetyl-CoA
(Amino or hydrazine residues)
Glutathione
Conjugation (GSH),
morphine
diazepam
isoniazid, dapsone
Glutathione
(Quinone or epoxide reactive intermediates)
Acetaminophen
Type of
Conjugation
Endogenous
Reactant
Examples
Glycine
GlycineAcyl -CoA
Conjugation
(Having carboxylic acid group)-minor pathway
Salicylic acid
nicotinic acid
Sulfation
(Phenolic or steroids)
Estrone
methyldopa



Phosphoadenosyl
phosphosulfate
S-Adenosyl
Methylation
methionine,
Dopamine
epinephrine, histamine
(Amines and phenols)

Water
Conjugation
Water
Benzopyrene
Leukotriene A4
Phenytoin
(highly lipophilic)
CYP (PHASE I)
4-hydroxyphenytoin (Slightly water soluble)
UGT+UDP-GA (PHASE II)
4-hydroxyphenytoin (highly water soluble)
beta-d-glucuronide
Drug metabolizing enzymes
Microsomal
Located in smooth ER
Catalyzes phaseI and
Phase II glucuronidation
INDUCIBLE BY DRUGS
Non microsomal
Cytoplasm and mitochondria
Catalyzes all conjugation
reactions except glucuronidation
NON- INDUCIBLE BY DRUGS
Hofmann Elimination

Inactivation of a drug in the body fluids by spontaneous
molecular rearrangement without the agency of enzyme (Non
enzymatic degradation in the plasma)
E.g., ATRACURIUM
- cleavage of the N-alkyl portion in the benzylisoquinoline
ENZYME INDUCTION
Repeated administration of certain drugs increases the
synthesis of microsomal enzymes - Chemically induce
P450
enhancing the rate
of its synthesis
reducing its rate of
degradation

Induction involves microsomal enzymes in liver and other
organs

It increases rate of metabolism by 2-4 fold

Various substrates inducing P450 are

Drugs: inducing CYP3A4 are
Barbiturates, carbamazepine, phenytoin, rifampin

Environmental pollutants: induce CYP1A1/2 enzymesactivation of procarcinogens
Eg: tobacco smoke, charcoal-broiled meat,
polycyclic hydrocarbons
Clinical relevance of enzyme induction
a)

Drug drug interactions:
Oral contraceptive and rifampicin :
Rifampicin induces the drug metabolizing enzyme of oral
contraceptives, thus enhancing the metabolism and leading to
contraceptive failure.

Phenytoin accelerates metabolism of vit.D3 and lead to
osteomalacia
c)
Therapeutic benefits:
To treat neonatal jaundice
- phenobarbitone can be given to infant soon after birth to
induce hepatic glucuronyl transferase
(Bilirubin is conjugated and excreted)
- In Cushing’s syndrome (Abnormally high levels of cortisol)
phenytoin may reduce the manifestations by enhancing
degradation of steroids
-
Chronic poisoning : faster metabolism of accumulated
poisonous substance
-
Vegetables like cabbage ,spinach etc can induce microsomal
enzymes and promotes the rapid elimination of the drugs
ENZYME INHIBITION

Certain drug substrates inhibit cytochrome P450 enzyme
activity
cimetidine and ketoconazole
bind tightly to the P450 heme iron
reduce the metabolism of endogenous substances
competitive inhibition.
Factors affecting drug biotransformation
AGE:
 Increased susceptibility to the pharmacologic or toxic activity
of drugs is seen in young and very old patients compared with
young adults .In neonates mainly due to diminished activity of
hepatic microsomal enzymes.





SEX:
dependent differences in drug metabolism exist in humans for
ethanol, propranolol, some benzodiazepines, estrogens, and
salicylates.
N-Demethylation of erythromycin F>M.
Propranolol oxidation M>F.
This is most probably due to hormonal differences
•
DIET AND ENVIRONMENTAL FACTORS

Charcoal-broiled foods and cruciferous vegetables induce
CYP1A enzymes

Grapefruit juice inhibits the CYP3A metabolism of
coadministered drug substrates

Cigarette smokers metabolize some drugs more rapidly than
nonsmokers because of enzyme induction
•DRUG DRUG INTERACTIONS DURING METABOLISM:

Enzyme-inducing drugs like
sedative-hypnotics, antipsychotics, anticonvulsants, the
antitubercular drug rifampin, and insecticides may increase
the requirement dose of drugs like warfarin
•DISEASES AND METABOLISM

Disease like alcoholic hepatitis, cirrhosis impair hepatic drug
metabolising enzymes
E.g. half-life of diazepam in patients with liver abnormality are
greatly increased, with a corresponding prolongation of their
effects
•GENETIC VARIATION (Pharmacogenetics)

Genetic factors that affect enzyme level leads to difference
in metabolism
 Defect
Enzyme
Involved
 N-Acetylation N-acetyl
transferase
Ester
hydrolysis


Plasma
cholinesterase
Drug
Clinical
Consequences
Isoniazid Peripheral
neuropathy
Sch
Prolonged
apnea
G6PD Deficiency –Hemolysis when exposed to certain
drugs like Sulphonamides , Salicylates
THANK YOU…!
5/9/2017