Lecture 3 - metabolism of drugs

Question 1

what is biotransformation?

Answer 1

major mechanism for drug elimination

Question 2

What is the product after the compund is broken down and what are their normal characteristics?

Answer 2

they are now called metabolites

more polar

Question 3

What happens when the metabolites are pharmacologically inert?

Answer 3

metabolism inactivates the effect on the body

Question 4

what are xenobiotics?

Answer 4

compounds that the organism cannot use as foods, and harmfull if they accumulate - no metabolic effect

Question 5

what are some examples of xenobiotics?

Answer 5

synthetic drugs

natural poisons

antibiotics

Question 6

how are xenobiotics detoxified?

Answer 6

by a set of xenobiotic-metabolizing enzymes

Question 7

what are some examples of xenobiotic metabolizing enzymes?

Answer 7

cytochrome P450 oxidases

UDP-glucoronosyl transferases

glutathione S-transferase

Question 8

how does the xenobiotic-metabolizing enzymes function?

Answer 8

they act in two stages

1. oxidizes the xenobiotic
2. conjugate water-soluable groups onto the molecule

Question 9

where is the majority of small-molecule drug metabolism carried out? and by what enzymes?

Answer 9

• liver
• cytochrome p450 enzymes -redox

Question 10

what are some possible consequences of biotransformation?

Answer 10

production of inactive metabolites w/

• increased or decreased potencies
• qualitatively different pharmacologic actions
• toxic metabolites
• active metabolites from inactive prodrugs

Question 11

What is a prodrug?

Answer 11

when the metabolites are more active than the parent drug

Question 12

What does the increase inpolarity mean for the metabolites?

Answer 12

they have a more rapid rate of clearance because of possible secretion by acids or base carriers in the kidney

tubular reabsorption

Question 13

Which organ is the major site of biotransformation?

Answer 13

liver

Question 14

What may effect the biotransformation of the drug?

Answer 14

prior administration of that drug

diet

hormonal status

genetics

diseases

age

developmental status

liver function

Question 15

How can we classify biotransformational reactions?

Answer 15

Phase I - nonsynthetic reactions

Phase II - synthetic reactions

Question 16

What happens during phase I in biotransformation reactions?

Answer 16

it involves enzyme-catalyzed biotransformations of the drug without any conjugations

Question 17

what reactions may occur in phase I

Answer 17

oxidations

reductions

hydrolysis reactions - frequently introduces a functional group that serves as the active center for sequential conjugation

Question 18

What happens during phase II?

Answer 18

conjugation reactions, which involves the enzyme-catalyzed combination of a drug with an endogenous substance

Question 19

What is required in phase II reactions?

Answer 19

• a functional group
• active center - as the site of conjugation with the endogenous substance
• energy indirectly for the synthesis of activated carriers, the form of the endogenous substance used in the conugation reaction

Question 20

What are the enzymes catalyzing phase I biotransformation reactions?

Answer 20

cytochrome P450

aldehyde and alcohol dehydrogenases

deaminases

esterases

amidases

epoxide hydratase

Question 21

What are the enzymes catalyzing phase II biotransformation reactions?

Answer 21

glucoronyl transferase

sulfotransferase

transacylases

acetylases

ethylases

methylases

glutathione transferase

Question 22

Whare can you finds the enzymes catalyzing phase I and II?

Answer 22

in multiple tissues and some in the palsma

Question 23

What is subcellular locations?

Answer 23

cytosol

mitochondria

endoplasmic reticulum

Question 24

Where are the enzymes that are inducible by drugs located?

Answer 24

endoplasmic reticulum

Question 25

What reactions does cytochrome P-450 catalyze?

Answer 25

• aromatic and aliphatic hydroxylations
• dealkylations at nitrogen, sulphur, and oxygen atoms
• heteroatom oxidations at nitrogen and sulphur atoms
• reductions at nitrogen atoms

Question 26

Which subfamily of cytochrome is responsible for half of the total CYP450 in the liver?

Answer 26

CYP3A

Question 27

which enzyme of the subfamily CYP3A is most abundant?

Answer 27

4

Question 28

what is the mechanism of reaction of CYP450?

Answer 28

drug is oxidized and oxygen is reduced to water

reducing equivalents are provided by NADPH - generation of this cofactor is coupled to CYP450 reductase

Question 29

what are some important genetic polymorphism in CYP450?

Answer 29

CYP2C and CYP2D is important in humasn

there are differences between racial and ethnic groups

Question 30

what can be an inductor?

Answer 30

drugs and endogenous substances-hormones

Question 31

what is metabolic tolerance?

Answer 31

when a drug induces its own metabolism

Question 32

In what ways can CYP450 be inhibited?

Answer 32

competitive or non-competitive

Question 33

What can cause inhibition of CYP450?

Answer 33

drugs: cimitidine, fluconazole, fluoxetine, erthromycin

Question 34

some drugs that inhibit CYP3A4 can also inhibit…?

Answer 34

drug effluc ttransporter P-glycoprotein

Question 35

What are the general feautures of glucoronyl transferase?

Answer 35

set of enzymes with overlapping specificities

involved in phase II reactions

catalyzes the conjugation of glucuronic acid to a variety of active centers - OH, COOH, SH and NH2

Question 36

What is the mechanism of reaction of glucoronyl transferase?

Answer 36

UDP-glucoronic acid, the active glucoronide donor is formed from UTP and glucose-1P

it will then catalyzr the conjugation to the active center of the drug

Question 37

where is glucoronyl transferase located?

Answer 37

in the endoplasmic reticulum

Question 38

how is the glucoronyl trransferace induced?

Answer 38

only phase II reaction that is inducible by drugs and is a possible site of drug interactions