Download Pengaruh Biotransformasi pada Keberasilan Terapi Jendela Terapi

Jendela Terapi
Pengaruh Biotransformasi
pada Keberasilan Terapi
Absorpsi Obat di Sal. Cerna
• Profil
Konsentrsi:
– Change in
elemination
rate
(Metabolism
& Eksretion)
– Metabolism
→ hepatic
clearance
Consequences of Drug Interaction
(metabolic change)
• Aliran darah GI
melalui Vena
Hepatika ke Hepar
– Firsfast effect
Clearance
Clearance hepatis
(intrinsic clearance)
• Clearance is the removal of drug by all
processes from the biological system.
– Metabolisme terjadi sebagian besar terjadi di
hati, sehingga akan berpengaruh pada
Clhepatis
For a high extraction drug (E > 0.7), the particular enzyme that metabolizes
this drug may be present in large amounts and drug processing is very rapid.
For a low extration drugs (E < 0.3), some drugs are cleared slowly,
Clh just depend on blood flow (Q)
1
Consequences of drug
concentration changes
• Drug failure
– Absorption
– Drug interaction doe to change of removal
Drug (inhibition & induction)
• Drug toxicity
Drug and xenobiotic metabolism
• Therapeutic view: essential to maintaince the drug
concentration in range of therapeutic window
– What are the metabolic or biotransformational processes that
can so dramatically influence drug concentrations and therefore
drug laction?
– How do these processes sense the presence of the drugs and
then remove these apparently chemically stable entities from the
body so effectively?
– What is the effect of illness, genetic profile and other patient
circumstances on the operation of these processes?
– How can these processes of removal of a drug lead to toxicity?
– What were these processes originally designed to achieve and
what is their endogenous function?
Drug Biotransformational
Systems – Origins and Aims
Sites of biotransforming
enzymes
Role of the Liver
CYP
• CYPs carry out a wide array of metabolic
activities
• CYPs have been shown to have highly
specific biomodulatory roles that are
distinct from high volume chemical
oxidation
• CYP-mediated endogenous
2
Role of the Liver
Contoh
Reaksi metabolisme
Hepatocit:
1. enzim pemetabolit terdapat di mitokondria bagian dari
Retikulum Endoplasik (RE),
2. Enzim RE (CYP) berperan penting dalam metabolisme
Siklus enterohepatika
Aims of biotransformation
• to assemble endogenous molecules and
then clear these and related chemicals
from the organism
• Metabolizing systems have developed
mechanisms to control balances between
hormone synthesis, and clearance
provides a dynamic equilibrium for the
organism to finely control the effects of
potent hormones such as sex-steroids.
Task of biotransformation
• Essentially, the primary function of
biotransforming enzymes such as CYPs
– is to ‘move’ a drug, toxin or hormone from the
left-hand side, to the right-hand side.
– This means making very oil-soluble molecules
highly water-soluble.
Phases I–III of biotransformation
• Phase I: Reaksi Fungsionalisasi
• Phase II: Reaksi Konjugasi
• Phase III:
– is a system of efflux pump molecules that can
even exclude unmetabolized drugs from the
gut almost as soon as they are absorbed.
3
Pendahuluan
How Phase I Systems
Metabolize Substrates
• Obat setelah terabsorpsi akan terdistribusi
• Sistem distribusi membawa xenobiotika ke hati
– Di hati akan terbawa ke hepatosit
– Xenobiotic akan terbawa sub selular hepatosit:
smooth endplasmic reticulum (SER; rough
endoplasmic reticulum (RER)
– SER memiliki struktur seperti tabung dengan diding
sangat lipofilik
– Xenobiotic non-polar akan terperangkap pada dinding
SER
– (terperangkap pada jalur Cyp-monooksigenase)
CYP- pada manusia
• CYP 1A series
– CYP 1A1
• This isoform binds and oxidizes planar aromatic, essentially flat molecules.
– CYP1A2
• Linked with oestrogen metabolism, as it is capable of oxidizing this series of
hormones
• CYP2 series (18-30%)
–
–
–
–
–
–
–
CYP2A6
CYP2B6
CYP2C8
CYP2C9
CYP2C19
CYP2D6
CYP2E1
• CYP3 series
– CYP3A4 and 3A5
4
Reaksi oksidasi (sistem monooksigenase yang tergantung pada CYP450)
Tahap 1: pengikatan RH
pada bentuk teroksidasi
(feri) dari CYP450
R-OH
Fe3+
Fe3+
IOI
R-H
Fe3+
OH
.
R
RH
H2O
Tahap 2: Reduksi elektron
pertama dri RH terikat
(feri) dari CYP450
terhadap bentuk ferro
F e 3+
NADPH + H+
NADPH + H+
RH
Fp
CYP b5
e
e
Tahap 3: pengitanan
oksigen pada ferro biner
CYP450
Fe 2+
+ 2 H*
RH
Fe3+
O2
O22RH
Fe3+
Fe2+
O2-
O2
RH
RH
Tahap 4,5,6: penyusunan
kembali elektron,
pengenalan elektron
kedua, penyisipan
oksigenberikutnya, dan
pelepasan produk
Bahasan
Induction of Phase I Systems
• Introduction
• Causes of accelerated clearance
• Enzyme induction
– Types of inducer
– Common features of inducers
• Mechanisms of enzyme induction
• Induction – general clinical aspects
Introduction
Induction of Phase I Systems
• The aim of drug therapy is to provide a stable,
predictable pharmacological effect that can be
adjusted to the needs of the individual patient for
as long is deemed clinically necessary.
– Pengobatan dimulai:
• Diharapkan mendapatkan respon seperti yg diinginkan
– Perubahan metabolisme sering mengakibatkan
perubahan respon
• Kadang diperlukan penyesuaian dosis
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Causes of accelerated clearance
• Acceleration of drug metabolism as a
response to the presence of certain drugs
is known as ‘enzyme induction’ and drugs
which cause it are often referred to as
‘inducers’ of drug metabolism.
– An adaptive increase in the metabolizing
capacity of a tissue’
– Accelerate the hepatic Clearance of Drug
6
Enzyme induction
•
Types of inducer
There are several drugs and chemicals capable of inducing hepatic
metabolism:
– Anticonvulsants, such as phenytoin, carbamazepine and phenobarbitone; these
induce many CYP isoforms, including 1A2, 2C9, 2C19 and 3A4.
– Steroids, such as dexamethasone, rednisolone and various glucocorticoids,
induce CYP3A4.
– Polycyclic aromatic hydrocarbons; these are found in atmospheric pollution,
cigarette smoke, industrial solvents and barbecued meat. These agents include
contaminants of foodstuffs and watercourses like dioxins and polycyclic
chlorinated biphenyls. These compounds induce the normally non-constitutive
CYP1A1 in the liver, as well as CYP1A2, which specializes in polycyclic aromatic
amines. Induction of CYP1A1 is also very strong in the lung in smokers and is a
standard marker for heavy tobacco use.
– Antibiotics, such as rifampicin and griseofulvin, induce most CYPs including 1A2,
2C9, 2C19 and 3A4.
– Recreational agents, such as nicotine in tobacco products, is a known inducer of
CYP1A2, and heavy alcohol consumption will induce CYP2E1.
– Herbal remedies; although more research must be conducted into the various
herbs on the market, St John’s Wort is the most clinically relevant and
investigated (CYP3A4).
Mechanisms of enzyme induction
• CYP1A1/1A2 induction
Mechanisms of enzyme induction
• CYP2B6 2C8/2C9 and 3A4
Mechanisms of enzyme induction
• The process by which enzyme induction occurs
has three main requirements:
– The hepatocyte must detect the presence of particular
potentially persistent lipophilic drugs and/or toxins
and correctly sense their concentration.
– The process of detection is translated into an
increase in the appropriate metabolic system within
the cell, which is capable of clearing the drug and/or
toxin as efficiently as possible.
– Complete (detection and action) system is dynamic
and reversible, so it is sensitive to further changes in
drug concentration.
Mechanisms of enzyme induction
• CYP2B6 2C8/2C9 and 3A4
Mechanisms of enzyme induction
• CYP2E1 induction
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Mechanisms of enzyme induction
• CYP3A4 induction
Induction – general clinical aspects
• From a clinical standpoint, important features of
enzyme induction can be summarized:
– The process is relatively slow, i.e. usually days or
even weeks;
– The potential changes in drug concentrations can be
great enough to cause treatment failure;
– The induction process is usually, but not always,
reversible over a similar time frame to its appearance,
although reversal can be slower;
– Where a patient is stabilized on a high ‘induced’ drug
dosage, if there is a treatment break of up to several
days, drug accumulation and toxicity will occur.
Induction – general clinical aspects
• Some of the most clinically relevant drug
interactions caused by enzyme induction are
described below:
– Anti-epileptic agents
• Drug combinations
• Drug withdrawal
• Other drug combinations
–
–
–
–
–
Phase I Enzyme Inhibition
OTC preparations
Anticoagulant drugs
Oral contraceptives/steroids
Antiviral/antibiotic drugs
Anti-cancer drugs
Introduction
• Menurunnya clearance obat
– Akumulasi obat
– Efek meningkat menuju efek toksik
• Interaksi ini dimungkinkan
– Inhibisi enzym pemetabolisme
8
Inhibition in General Aspects
9