Drug Metablism: Phase I and II Metabolism

Question 1

Why is the volume of distribution important for clinical reasons?

Answer 1

If you know the apparent volume of distribution and have a target, you can then arise at an optimal dose to give the patient.

Question 2

Why should you not administer a dose of a drug to a patient that is above the correct dose?

Answer 2

If you administer a dose to a patient that is above the correct dose, you produce reactive products that are generally toxic and cause side effects. These reactive products are then taken up by phase II which makes them non-toxic and excretes them out of the body.

Question 3

What is the acronym for Absorption, Distribution, Metabolism and Excretion (Elimination)?

Answer 3

(ADME)

Question 4

What is the process of absorption when you take a drug?

Answer 4

Drug is absorbed form the site of administration - entry into the plasma.

Question 5

What is the process of distribution when you take a drug?

Answer 5

Drug reversibly leaves the bloodstream and is distributed into interstitial and intracellular fluids.

Question 6

What is the process of metabolism when you take a drug?

Answer 6

Drug transformation by metabolism by the liver and other tissues.

Question 7

What is the process of excretion (Elimination) when you take a drug?

Answer 7

Drug and/or drug metabolites excreted in urine, faeces or bile.

Question 8

What is the definition of drug metabolism?

Answer 8

It is the enzymatic conversion of a drug to another chemical entity.

Question 9

What is the most important drug-metabolising organ?

Answer 9

The liver

Question 10

Other than the liver what other organs also contribute to the metabolising of drugs?

Answer 10

The kidney, gut mucosa, lungs and skin also contribute.
(The liver is the main site for drug metabolism but sometimes it also occurs in kidney particularly in patients with compromised liver function).

Question 11

What reduces the bioactivity of drugs when administered by the enteral (oral) route?

Answer 11

Metabolism in the liver (and/or gut).

Question 12

How many phases does drug metabolism occur in, what are the names of these and where do they occur?

Answer 12

2 phases:
- Phase I and Phase II
- Both phases take place mainly in the liver
(Generally drug metabolism occurs in 2 phases but sometimes it goes straight to stage 2.

Question 13

Where are hepatic drug-metabolising enzymes located?

Answer 13

Hepatic drug-metabolising enzymes (microsomal enzymes) are embedded in the smooth endoplasmic reticulum of the liver hepatocytes.
(Drug metabolism is dependent on the enzymes in the liver hepatocytes).

Question 14

Why are non-polar molecules metabolised more readily than polar molecules?

Answer 14

Non-polar molecules cross the plasma membrane to be metabolised more readily than polar molecules - logical since non-polar and lipophilic drugs can more readily cross membranes in contrast to hydrophilic drugs.

Question 15

What happens in Phase I?

Answer 15

Change in drug by oxidation, reduction or hydrolysis.
Oxidation is accomplished by cytochrome P450 enzymes, microsomal haem proteins. During oxidation the drug molecule incorporates one atom of O2 to the drug to form a hydroxyl group.
Cytoplasmic enzymes can metabolise the drug.
Hydrolytic reactions - ester an amide bonds are susceptible to hydrolysis.
Usually form chemically reactive metabolites that can be pharmacologically active and/or toxic
(Phase I reactions generally produce an active metabolite).

Question 16

What is an example of when oxidation I phase I can produce harmful metabolites?

Answer 16

Paracetamol is oxidised to form NAPQI.
In the right quantities this can detoxified during phase 2 but if there is too much it can cause tissue damage, particularly in the liver.

Question 17

What is P450 activity genetically determined by?

Answer 17

• Some persons lack such activity this leads to higher drug plasma levels (adverse actions)
• Some persons have high levels this leads to lower plasma levels (and reduce drug action).

Question 18

What are liver P450 systems comprised of?

Answer 18

Cytochrome P450 enzymes are haem proteins which comprise a large superfamily.
74 CYP gene families have been described, CYP1, CYP2 an CYP3 involved I drug metabolism in the human liver.

Question 19

Other drugs can interact with the P450 systems, what can they induce?

Answer 19

Either induce activity (tolerance, pharmacokinetic antagonism).

Question 20

Is the amount of enzymes in the liver P450 systems the same in everyone?

Answer 20

No, the amount of these enzymes present varies or each individual.
Ethanol can reduce the bioavailabilty of the cells that are present.

Question 21

Drug oxidation by the monooxygenase P450 system required what?

Answer 21

The monooxygenase P450 system requires the drug, the p450 enzyme, molecular oxygen, NADPH and flavoprotein.

Question 22

What is the process of the monooxygenase p450 system?

Answer 22

P450 ferric iron combines with the drug and receives an electron from NAPH-P450 reductase, reducing the iron to Fe2+.
Fe2+ combines with O2 followed by a second electron from NADPH-P450 reductase or cytochrome b5 (5 is subscript).
This forms the Fe2+-OOH-drug complex. This combines with another proton to yield H2O and (FeO)3+ - drug .
(FeO)3+ extracts a hydrogen atom from the drug and eventual liberation of the oxidised drug.

Question 23

What are the processes in Phase II of drug metabolism?

Answer 23

Phase II reactions involve the combination of the drug with one of several polar molecules to form a water-soluble metabolite.
Conjugation usually involves the reactive group produced by Phase I.
Usually terminates all biological activity.
Conjugated produces can be readily excreted via the kidney.
( Phase I is the dangerous phase in terms of accumulation of metabolites. To prevent this accumulation, the phase II reactants attach another molecule onto the drug which switches off any type of pharmacological activity, detoxifies it and packages it up, making it ready to be eliminated through the urine. Switches off any pharmacological or biological activity.

Question 24

Phase II Reactions involve the addition of naturally present molecules in the body to the drug. What are the different molecules that add to the drug and how is it involved in the enzyme and co-factor?

Answer 24

Glucronidation - Uridine disulphate-glucuronosyltransferases - Uridine diphosphate-glucuronic acid.
Glutathone conjugation - glutathione S-transferase - glutathione
glycine conjugation - acetyl Co-enzyme As - glycine
Methylation - methyltransferase - S-adenoyl- L-methionine
Sulphation - sulfotransferases- 3’-phosphoadenosine-5’-phosphosulfate
Acetylation - N-acetyltransferases - Acetyl Coenzyme A
(glucuronidation makes it water soluble and packages it up. The others are a little less predominant).

Question 25

Some drugs can go directly to phase II metabolism (and also have metabolites that are pharmacologically active). What is an example of this?

Answer 25

Codine is an opiate. Around 10% of codine is metabolised to morphine. It doesn’t go through phase 1 and instead goes straight to phase 2 metabolism.
If a drug goes directly to stage 2, sometimes they can metabolise into pharmacologically active metabolites.