Drug Metabolism

Question 1

Why would you want a drug to be lipophilic?

Answer 1

So drugs can access tissues - therapeutic effect

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Question 2

Why would you want a drug to be water soluble?

Answer 2

Retained in the blood and delivered to excretion sites

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Question 3

We design relativley lipid soluble drugs

Answer 3

Body alters the drug to make it less lipid soluble and easier to excrete.

The process of metaboiksm invovles conversion of drugs (usually quite lipid soluble) to metaboliites (usually less lipid soluble and easeir oto excrete)

Question 4

Drug metabolism involves two kinds of biochemical reaction

Answer 4

Phase1 - main aim to introduce a reactive grouop tot he drug (increase polarity()

Phase 2 - main aim is to add a water soluble conjugate tot he reactive group

Question 5

Phase 1 metabolism

Answer 5

Oxidation/reduction creates new functional groups
Hydrolysis unmasks them

NOTE: functional group serves as a point of attachment for phase 2 reactions

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Question 6

Most common phase 1 metabolism

Answer 6

Oxidation (often start with hydroxylation)
Mainly in the liver
Different subtypes metabolism different drugs
Cytochrome P450 S.E.R, 57 enzymes

NOTE: levels of enzymes are different in different people

Question 7

Where does oxidation occur with aspirin?

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Answer 7

Acetyl group

Question 8

Nictoine —> cotinine
Oxidation, reduction or hydrolysis?

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Answer 8

Oxidation

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Question 9

Cocaine —> ecgonine methyl ester
Oxidation, reduction or hydrolysis?

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Answer 9

Hydrolysis

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Question 10

chlorla hydrate —> trichloroethanol
oxidation, reduction or hydrolysis?
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Answer 10

REduction

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Question 11

Active parent drug —>
Active parent drug —>
Inactive parent drug —>

Answer 11

Inert metabolite (no effect on body)
Active metabolite (prolongs effects)
Active metabolite (prodrug - inactive on administration, needs metabolism to activate)

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Question 12

Phase 2 metabolism

Answer 12

Adding side chains onto drug
Glutathione conjugation
Glucuronidation
Acetylation
Sulfation

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Question 13

Most common phase 2 metabolism

Answer 13

Glucuronidation

Glucuronidation is low affinity/high capacity - more likely to occur at high drug dosages

Question 14

Sulfation

Answer 14

High affinity/low capacity - more likely to occur at low drug dosages

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Question 15

Glucathione conjugation

Answer 15

Drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate

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Question 16

How do you convert paracetamol to an electrophile?

Answer 16

Oxidation can mean gaining oxygen or losing hydrogen

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NOTE: Paracetamol overdose = use up all of GSH conjugate stores. Left with incredibly reactive NAPQI which reacts with proteins in the liver —> massive liver dysfunction (electorphiles are extremely reactive)

Question 17

Acetylation

Answer 17

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Question 18

Methylation

Answer 18

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Question 19

Amino acid conjugation

Answer 19

Two reactions possible:

• with carboxylic acid group of AA
• with amino group of AA

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Question 20

Importance of drug metabolism

Answer 20

The biological half-life of the chemical is decreased
The duration of exposure is reduced
Accumulation of the compound in the body is avoided
Potency/duration of the biological activity of the chemical can be altered
The pharmacology/toxicology of the drug can be governed by its metabolism