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)
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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
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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.
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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
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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
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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
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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
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Inhibition in General Aspects
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