Biotransformasi

dr.Tri Widywati,M.Si, Ph.D-dr. Sake Juli Martina, SpFK

BBS2_FT_K4
 Objektif Pembelajaran
1. Defenisi biotransformasi
2. Fase I biotransformasi
3. Fase II biotransformasi
4. Enzim yang terlibat
5. Sitokrom P450 dan isoform
6. Faktor genetik dalam biotransformasi obat
 Pendahuluan
Xenobiotics- substances foreign to body

Drugs, Processed food, Food additives, Cosmetic

products, Environmental pollutants, Agrochemicals
 Eliminasi

Eksresi Metabolisme
(Biotransformasi)

4
 Defenisi biotransformasi

• Reaksi biokimia yang terlibat dalam proses perubahan xenobiotika

menjadi turunan yang lebih non polar dengan tujuan xenobiotika
lebih mudah dieleminasi dari dalam tubuh organisme
Non polar lipid soluble (hidrofobik-lipofilik) polar lipid insoluble
(hidrofilik-lipofobik)->metabolit hidrofilik
Highly polar drugs: less biotransformed and excreted unchanged :
streptomycin, neostigmine, pancuronium etc
6
Termination of Drug Action

atropine tropic acid and tropine

Activation of Prodrug

L-dopa Dopamine
Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine

activation of prodrug
terfenadine

fexofenadine
Some Xenobiotics Are Metabolized to Carcinogenic Agents

carcinogenesis

• 3,4 Benzopyrene
• Aflatoxin
• N-Acetylaminoflluorene

Metabolites of these agents interact with DNA

 Small Amounts of Acetaminophen is Converted to the
Reactive Metabolite N-Acetylbenzoquinoneimine

bioactivation

Bioactivation of acetaminophen; under certain conditions, the electrophile N-acetylbenzoquinoneimine reacts with tissue
macromolecules, causing liver necrosis.
 Thalidomide is a Teratogen

• Fetal malformations in humans, monkeys, and rats occur due to

metabolism of the parent compound to a teratogen.
• This occurs very early in gestation.
 Fase Biotransformasi

 Phase I / Non synthetic / Functionalization

 A functional group is generated
 Metabolite – active or inactive

 Phase II / Synthetic / Conjugation

 An endogenous radical is conjugated
 Metabolite is usually inactive
 Patterns of Drug Metabolism

• Parent molecule  Phase 1 metabolism

• Phase 1 metabolite  Phase 2 metabolism

• Parent molecule  Phase 2 metabolism

• Phase 2 metabolite  Phase 1 metabolism

 Biotransformation
Phase - I
- Oxidation : Morphin,
acetaminophen
- Reduction : Chloramphenicol,
Clonazepam
- Hydrolisis : Aspirin, Lidocain
 Biotransformation
• PHASE- II
- Conjugation : Morphin
(process glucuronidation),
INH (process acetilation),
Enzim yang terlibat
Enzymes catalyzing phase I biotransformation reactions

– cytochrome P-450
– aldehyde and alcohol dehydrogenase
– deaminases
– esterases
– amidases
– epoxide hydratases
Enzymes catalyzing phase II biotransformation reactions

– glucuronyl transferase (glucuronide conjugation)

– sulfotransferase (sulfate conjugation)
– transacylases (amino acid conjugation)
– acetylases
– ethylases
– methylases
– glutathione transferase.
Location of these enzymes:
• – numerous tissues
– some are present in plasma.

• Subcellular locations include:

– cytosol
– mitochondria
– endoplasmic reticulum

• Only those enzymes located in the endoplasmic reticulum

are inducible by drugs
Sitokrom P450 dan isoform
 Cytochrome P-450 monooxygenase
(mixed function oxidase)

• A large number of families (at least 18 in mammals) of

cytochrome P-450 (abbreviated “CYP”) enzymes exists
each member of which catalyzes the biotransformation of a
• unique spectrum of drugs
some overlap in the substrate specificities.
•

• This enzyme system is the one most frequently involved

in phase I reactions.
• The cytochrome P-450 families are referred to using an arabic
numeral, e.g., CYP1, CYP2, etc.

• Each family has a number of subfamilies denoted by an upper

case letter, e.g., CYP2A, CYP2B, etc.

• The individual enzymes within each subfamily are denoted by

another arabic numeral, e.g., CYP3A1, CYP3A2, etc.
Cytochrome P-450 catalyzes numerous reactions

– aromatic and aliphatic hydroxylations

– dealkylations at nitrogen, sulfur, and oxygen atoms
– heteroatom oxidations at nitrogen and sulfur atoms
– reductions at nitrogen atoms
– ester and amide hydrolysis
• The CYP3A subfamily is:

– responsible for up to half of the total cytochrome P-

450 in the liver

– accounts for approximately 50% of the metabolism of

clinically important drugs.

– CYP3A4 is a particularly abundant enzyme.

representative
P450 isozymes.
Localization

• The primary location of cytochrome P-450 is the liver,

• Other tissues, including:

– the adrenals
– ovaries and testis
– tissues involved in steroidogenesis and steroid metabolism.

• The enzyme's subcellular location is the endoplasmic

reticulum.
 INHIBITION OF DRUG METABOLISM
One drug can inhibit the metabolism of another drug
↑ in circulating levels of slowly metabolised drug
Prolongation or potentiation of its effects

Consequences
 Precipitate toxicity of the object drug. can
 be therapeutically beneficial.
Eg:
aversion of alcohol with disulfiram
 Valproate
 Ketoconazole
 Cimetidine
 Ciprofloxacin
 Erythromycin
 INH

 Code – Vitamin K cannot cause enzyme inhibition.

MICROSOMAL ENZYME INDUCTION
 Drugs, insecticides, carcinogens will induce
the synthesis of microsomal enzyme proteins
 Accelerated metabolism and reduced
pharmacological response

 Consequences
 Drug- drug interactions
 Can lead to toxicity. Eg: Alcoholics more
prone to hepatotoxicity of paracetamol due to↑
production of NABQI
 Therapeutic benefit. Eg: To treat neonatal
jaundice
 Decreased duration of action. Eg: OCP (oral
contraceptive pills) failure

 Griseofulvin
 Phenytoin, Primidone
 Rifampicin
 Smoking
 Carbamazepine
 Phenobarbitone
 First Pass Metabolism
 Presystemic metabolism/ First pass effect
 Metabolism of a drug during its passage from the
site of absorption into the systemic circulation.
 ↓ed BA
 ↓ed therapeutic response
 SITES
 Gut wall
 Gut lumen
 Liver (major site)
 Lungs
 Skin
 FACTORS AFFECTING BIOAVAILABILITY

Gut Portal Liver Systemic

lumen circ. circ.
Drugs in Drug Drug :
gut absorbed absorbed intact
intact and escaping
first-past metab.

100 80 60
60 20

Drug extracted
first-past
• Fraction absorbed is 0.8
• The hepatic extraction ratio : 0.75

* Bioavail. = fraction absorbed × ( 1 – extract. ratio)

35
Faktor genetik dalam biotransformasi obat
 Perubahan Genetika yang Mempengaruhi Metabolisme Obat

Enzim Perubahan Genetika Konsekuensi Klinis

CYP2C9 1-5% ras Kaukasia dan <1% Afro-Amerika Individu dengan bentuk CYP2C9 yang kurang aktif
dan orang Korea memiliki bentuk sangat sensitif terhadap efek warfarin dan beresiko
CYP2C9yang kurang aktif mengalami toksisitas dari obat-obat yang dimetabolisme
oleh CYP2C9
CYP2C19 Sampai 20% orang Asia dan 2-5% ras Kurangnya CYP2C19 dapat meningkatkan efek dan
Kaukasia kekurangan enzim CYP2C19 toksisitas dari obat-obat yang dimetabolisme oleh
CYP2C19
CYP2D6 5-10% ras Kaukasia, 1-3% Afro-Amerika, Individu yang tidak memiliki CYP2D6 dapat mengalami
dan 1-3% oranag China tidak memiliki toksisitas dari obat-obat yang metabolisme utamanya
enzim CYP2D6 oleh CYP2D6 (contoh : antidepresan trisiklik) meskipun
pada dosis kecil. Selain itu juga memberikan respon
yang subterapi terhadap obat yang diaktivasi oleh
CYP2D6 (misal kodein)
NAT2 Hingga 50% ras Kaukasia, 10% orang Rendahnya atau tidak adanya aktivitas NAT2 dikaitkan
Jepang, dan 80-90% orang Mesir dan dengan efek lupus eritematosus sistemik dari
Maroko kekurangan enzim NAT2 prokainamida dan hidralazin; neuropati perifer dari
isoniazid, hidralazin, dan dapson; dan leukopenia,
nausea, vomiting, vertigo, dan sakit kepala akibat
sulfasalazin.
Terimakasih