By Duy Thai: www.geocities.com/d.

thai 1997 Pharmacology Semester 1 page 1 of 4

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 metabolise 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.
• Say 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 SER 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
anaesthetic) 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 metabolised 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.
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 2 of 4

• Some of the drug will pass through the gut without being absorbed and excreted.
• Some of the drug will be metabolised when passing through the gut wall. Penicillin is an example of a
drug which is metabolised 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 metabolised (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
metabolised 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 usually
expressed as a percentage of the amount of drug eliminated over the amount of drug that entered
the organ.
• e.g. 60mg of a drug enters the liver from the portal circulation. After first pass metabolism, only
10mg of the drug enters the systemic circulation. 50mg of the drug has been eliminated by the
liver. The extraction ration is 50/60 = 83%
• If there is a very small change in bioavailability, the oral dose of the drug approximates the IV dose (an IV dose of
drug has a 100% bioavailability).
• If the bioavailability is very small, virtually all of the drug is eliminated in the first pass effect, so that the oral dose
must be much higher. Often, it is better to find alternative ways of administration to bypass the gut and liver.
• E.g. Glycerol trinitrate is eliminated very rapidly by the liver, hence it is given sublingually.
• The veins under the tongue drain directly to the vena cava.
• Sometimes the first pass effect is useful
• E.g. Salbutamol.
• Salbutamol is a β2 agonist. We want it to work locally at the lungs, but sometimes salbutamol is
swallowed (salbutamol is administered by a puffer).
• Salbutamol can thus enter the gut and passes through the liver.
• If salbutamol were allowed to enter the systemic circulation, it would have adverse
effects on the heart.
• Luckily, salbutamol undergoes a large degree of first pass metabolism in the liver, so
that the amount entering the systemic circulation is minimal.
• The following drugs have a high first pass clearance:
• Aspirin
• Morphine
• Salbutamol
• Verapamil

Phase I reaction – Processes

• The main phase I reactions involve:
• Oxidation
• Reduction
• Hydrolysis
• The most important phase I reaction is oxidation involving the mixed function oxidase system.
• This is an enzyme complex requiring:
• A reducing agent (NADPH)
• Molecular oxygen
• NADPH cytochrome p450 oxidase
• Cytochrome p450
• Many drugs can act to induce or inhibit the cytochrome p450 enzyme.
• Drugs which inhibit cytochrome p450 will prevent the metabolism of other drugs which rely on this
enzyme.
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 3 of 4

• E.g. Cimitidine blocks p450. If it is administered with digitoxin, digitoxin concentrations will
remain high for longer periods. Digitoxin is dangerous because it has a narrow therapeutic
window, so any factors which could lead to an elevation of digitoxin levels is a potential hazard.
• Drugs which induce the production of cytochrome p450 will accelerate the metabolism of drugs which
rely on this enzyme.
• Examples of drugs which induce p450:
• Polycyclic aromatic hydrocarbons
• Glucocorticoids, macrolide antibiotics, anticonvulsants
• Ethanol
• Benzopyrene (found in cigarette smoke, a possible carcinogen when activated by the
liver)
• PCB
• Barbituates (Phenobarbitone)
• Hence, this is an important factor which needs to be kept in mind when using drug combinations
• Mechanisms of induction (of cytochrome p450)
• Induction involves a drug binding to a cytosolic receptor.
• This drug-receptor complex is translocated to the nucleus where it stimulates the gene transcription and
the increased production of protein.
• Mechanisms of inhibition (of cytochrome p450):
• Poorly understood
• Probably via substrate competition
• A smoker can induce enzymes in the liver and also in other organs, thus increasing the metabolism and breakdown
of drugs. Hence, it important to know whether a person is a smoker or not when prescribing drugs.

Phase II reactions – Processes

• The enzymes involved in phase II reactions are all known as tranferases.
• E.g. UDP glucoronide transferase catalyses the conjugation of a drug with glucoronide.
• If a toxic phase I product is produced, the body must rely on the phase II reaction to detoxify it.
• Therefore, if a drug which has a toxic phase I product is taken at high doses, the liver will be unable to
handle the increased levels of toxic products and hence will not be able to detoxify them in phase II
reactions. The liver is dependent on the availability of endogenous molecules taking part in the
detoxification reactions.
• Conjugation usually allows for easier excretion since the drug is converted into a more hydrophilic form.

Why is first pass clearance important?

• Lets take an example of a drug which has a low extraction ratio by the liver:
• E.g. Theophyline ER = 2% Bioavailability = 98%
If liver enzymes are induced 2 fold ER = 4% Bioavailability = 96%

• Now, lets take an example of a drug which has a high extraction ratio
• E.g. Verapamil ER = 90% Bioavailability = 10%
• If liver enzymes are induced 2 fold ER = 95% Bioavailability = 5%

• What this shows is that for drugs with a low extraction ratio, a change in enzyme activity will lead to a small
change in bioavailability. On the other hand, a drug which has a high extraction ratio will have a large change in
bioavailability when enzyme activity is altered.
• This means that, for high extraction drugs, liver enzyme activity is the major determinant of bioavailability.
Summary
• Drug – drug interactions
• Some drugs may inhibit/induce the enzymes required for the metabolism of the other drug. Hence the
clearance of the other drug may be reduced or increased respectively.
• The oral does and IV dose is altered depending on bioavailability
• For high bioavailability, oral dose ≈ IV dose
• For low bioavailability, oral dose > IV dose
• Patients with liver disease will not metabolise drugs as effectively as someone with a healthy liver.
• Other factors:
• Age
• Children may not yet have the full repertoire of enzymes required for metabolism
By Duy Thai: www.geocities.com/d.thai 1997 Pharmacology Semester 1 page 4 of 4

• Elderly people have a natural degradation of liver and renal function, hence leading to
impaired clearance of drugs.
• Some drugs may be stored in the liver, e.g. diazepam. Liver degradation can
lead to reduced diazepam storage.