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الكلية كلية الصيدلة
القسم فرع الادوية والسموم
المرحلة 3
أستاذ المادة صباح نعمه كامل الثامر
5/23/2011 4:06:59 AM
DRUG METABOLISM 1
Drug metabolism
• Biotransformation is the same as metabolism.
• Metabolism of a drug involves the modification of a drug via its interaction with endogenous metabolic enzymes.
• These enzymes were not designed to handle the drugs specifically. They were designed to metabolize endogenous chemicals, not artificial drugs. It just so happens that the enzymes choose to accept a drug as being a substrate. The enzymes are not very selective.
• Hence, there is competition for enzymes.
• e.g. we have enzyme A.
• Substance A is the normal endogenous substrate for enzyme A.
• We now have a drug (drug 1) which can act as a substrate for enzyme A.
• Drug 1 and substance A will compete for the enzyme. Hence, the physiological condition of a patient may affect the metabolism of drug 1 because of varying levels of substance A in the body.
• If there is lots of substance A, then metabolism of drug 1 will be reduced and vice versa.
• If another drug is added (drug 2) which is also a substrate for this same enzyme, we get a 3 way competition for the enzyme. Hence, when giving drug combinations, it is important to know how one drug will affect the metabolism of the other.
• Usually, enzymatic modification abolishes a drugs activity. There are exceptions.
• Drug metabolism:
• Reduces the drugs effect
• Often inactivates the drug
• Makes the drug more polar so that it can be readily excreted
• Occurs mainly in the Smooth endoplasmic reticulum of the liver hepatocytes.
• Can also occur in other sites:
• Kidney
• Lungs
• GIT
• Skin
• Occurs in 2 phases:
• Phase I reaction
• Phase II reaction
Phase I reactions
• Phase I reaction usually, but not always occur before phase II reactions.
• It involves the addition of some reactive functional group to the drug.
• This reactive site on the drug serves as a point of attack by a conjugating system which occurs in phase II.
• 3 main types of phase I reactions:
• Oxidation
• Reduction
• Hydrolysis
• Sometimes, reactions in phase I can inactivate a drug before phase II. e.g. Phase I hydrolysis of procaine (a local anesthetic) inactivates the drug.
• Sometimes, reactions in phase I can turn an inactive pro-drug into an active one.
• Sometimes, the reaction can turn a harmless chemical into a toxic one.
Phase II reactions
• Combines some endogenous substrate which is added to the phase I product (conjugation).
• Phase II reactions are usually the detoxification step.
• Sometimes, phase II reactions occur before phase I.
• e.g. Isoniazid undergoes acetylation first (conjugation of the drug with Acetyl CoA) and then Hydrolysis.
• There are some drugs which bypass phase I reactions and go straight to phase II.
• There are also drugs which are not metabolized at all (do not undergo phase I or II reactions) and are excreted unchanged.
Factors affecting bioavailability - First pass effect
• When a drug is administered orally, it enters the gut lumen.
• Some of the drug will pass through the gut without being absorbed and excreted.
• Some of the drug will be metabolized when passing through the gut wall. Penicillin is an example of a drug which is metabolized by the gut (also, peptide hormone drugs).
• The amount of drug absorbed intact (often considerably less than the original dose) will enter the portal vein and go to the liver.
• As the drug passes through the liver for the first time, some of the drug will be metabolized (first pass
effect). Thus, the amount of drug which finally enters the systemic circulation is very small compared to the amount of drug administered.
• Some important terms:
• Bioavailability
• The bioavailability is the amount of drug which actually enters the plasma. It is usually expressed as a percentage of the original dose.
• e.g. An oral dose of 50mg results in only 10mg entering the plasma (40mg has been metabolized or lost). Thus, the bioavailability if 10/50 = 20%
• Extraction ration
• The extraction ratio is a measure of how effectively an organ can eliminate a drug. It is
المادة المعروضة اعلاه هي مدخل الى المحاضرة المرفوعة بواسطة استاذ(ة) المادة . وقد تبدو لك غير متكاملة . حيث يضع استاذ المادة في بعض الاحيان فقط الجزء الاول من المحاضرة من اجل الاطلاع على ما ستقوم بتحميله لاحقا . في نظام التعليم الالكتروني نوفر هذه الخدمة لكي نبقيك على اطلاع حول محتوى الملف الذي ستقوم بتحميله .
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