DRUG METABOLISM AND EXCRETION

Question 1

What is metabolism?

Answer 1

The chemical processes that occur within a living organism in order to maintain life

Question 2

What is conjugation?

Answer 2

The addition of chemical groups to drugs during metabolism

Question 3

What does phase 1 metabolism consist of? The

Answer 3

Oxidation, hydrolysis, hydroxylation and deamination

Question 4

What’s the key enzyme in phase 1 metabolism?

Answer 4

CYP450

Question 5

What does CYP450 do?

Answer 5

It discontinuously metabolises the compounds within the body

Question 6

What’s important structurally about CYP450?

Answer 6

It has Fe3+ attached to it

Question 7

Outline how CYP450 works to make a drug more polar and easier to excrete?

Answer 7

The Fe3+ in the enzyme can accept an electron from NADPH so that CYP450 contains Fe2+ now. This allows the enzyme to react with oxygen and protons to produce water. This reaction causes Fe2+ to turn back to Fe3+

Question 8

What are some examples of things that can induce or inhibit CYP450?

Answer 8

Cigarette smoke and alcohol can induce it to elevate metabolism whilst grapefruit juice can inhibit it
It’s important to know this as it can affect the toxicity or the drug and the therapeutic effects

Question 9

What happens in phase 2 metabolism of drugs?

Answer 9

This is a detoxification reaction where conjugation occurs within the liver. This also makes the drug more polar, in hope to drive elimination via the kidneys rather than bile

Question 10

What are the 3 types of conjugation reaction?

Answer 10

Glucoronidation - adding UDP-glucoronic acid
Amino acid conjugation
Sulfoconjugation - adding sulphate esters

Question 11

What is bioavailability?

Answer 11

The amount of drug left to have an effect in the body - the amount that reaches systemic circulation

Question 12

What is first pass metabolism?

Answer 12

When the concentration of the drug is greatly reduced before it reaches systemic circulation - this is greatly related to metabolism in the liver

Question 13

What is the ‘single compartment model’?

Answer 13

This model assumes that the drug can enter or leave the body (ie, the model is “open”), and the entire body acts like a single, uniform compartment.

Question 14

What are some limitations to the single compartment model?

Answer 14

It’s oversimplified, it assumes the rates of absorption metabolism and secretion are directly proportional to the drug concentration within the compartment

Question 15

When will you hit a steady state of a drug if you use repeat dosing?

Answer 15

3-5 doses in

Question 16

What’s the two-compartment model?

Answer 16

A model that divides into the central and peripheral compartment
The peripheral compartment consists of tissues which usually have a slower drug distribution

Question 17

What are some limitations of the 2-compartment model?

Answer 17

Some drugs are not equally soluble across all tissues

Question 18

What is zero order kinetics?

Answer 18

the body will break it down at the same rate until all of it is gone, unlike first order kinetics where the rate at which a drug is broken down is proportional to the concentration given. - this makes drug metabolism predictable

E.g. if drug concentration is 7 but we have 4 elimination pumps then the rate of elimination will be 4… no matter how much more drug you add, the rate of elimination will remain the same - when drug elimination occurs at a constant rate

Question 19

What do we call it when a high drug concentration leads to a higher rate of elimination?

Answer 19

First order kinetics