Lecture 3 - metabolism of drugs Flashcards Preview

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1
Q

what is biotransformation?

A

major mechanism for drug elimination

2
Q

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

A

they are now called metabolites

more polar

3
Q

What happens when the metabolites are pharmacologically inert?

A

metabolism inactivates the effect on the body

4
Q

what are xenobiotics?

A

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

5
Q

what are some examples of xenobiotics?

A

synthetic drugs

natural poisons

antibiotics

6
Q

how are xenobiotics detoxified?

A

by a set of xenobiotic-metabolizing enzymes

7
Q

what are some examples of xenobiotic metabolizing enzymes?

A

cytochrome P450 oxidases

UDP-glucoronosyl transferases

glutathione S-transferase

8
Q

how does the xenobiotic-metabolizing enzymes function?

A

they act in two stages

  1. oxidizes the xenobiotic
  2. conjugate water-soluable groups onto the molecule
9
Q

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

A
  • liver
  • cytochrome p450 enzymes -redox
10
Q

what are some possible consequences of biotransformation?

A

production of inactive metabolites w/

  • increased or decreased potencies
  • qualitatively different pharmacologic actions
  • toxic metabolites
  • active metabolites from inactive prodrugs
11
Q

What is a prodrug?

A

when the metabolites are more active than the parent drug

12
Q

What does the increase inpolarity mean for the metabolites?

A

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

tubular reabsorption

13
Q

Which organ is the major site of biotransformation?

A

liver

14
Q

What may effect the biotransformation of the drug?

A

prior administration of that drug

diet

hormonal status

genetics

diseases

age

developmental status

liver function

15
Q

How can we classify biotransformational reactions?

A

Phase I - nonsynthetic reactions

Phase II - synthetic reactions

16
Q

What happens during phase I in biotransformation reactions?

A

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

17
Q

what reactions may occur in phase I

A

oxidations

reductions

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

18
Q

What happens during phase II?

A

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

19
Q

What is required in phase II reactions?

A
  • 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
20
Q

What are the enzymes catalyzing phase I biotransformation reactions?

A

cytochrome P450

aldehyde and alcohol dehydrogenases

deaminases

esterases

amidases

epoxide hydratase

21
Q

What are the enzymes catalyzing phase II biotransformation reactions?

A

glucoronyl transferase

sulfotransferase

transacylases

acetylases

ethylases

methylases

glutathione transferase

22
Q

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

A

in multiple tissues and some in the palsma

23
Q

What is subcellular locations?

A

cytosol

mitochondria

endoplasmic reticulum

24
Q

Where are the enzymes that are inducible by drugs located?

A

endoplasmic reticulum

25
Q

What reactions does cytochrome P-450 catalyze?

A
  • aromatic and aliphatic hydroxylations
  • dealkylations at nitrogen, sulphur, and oxygen atoms
  • heteroatom oxidations at nitrogen and sulphur atoms
  • reductions at nitrogen atoms
26
Q

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

A

CYP3A

27
Q

which enzyme of the subfamily CYP3A is most abundant?

A

4

28
Q

what is the mechanism of reaction of CYP450?

A

drug is oxidized and oxygen is reduced to water

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

29
Q

what are some important genetic polymorphism in CYP450?

A

CYP2C and CYP2D is important in humasn

there are differences between racial and ethnic groups

30
Q

what can be an inductor?

A

drugs and endogenous substances-hormones

31
Q

what is metabolic tolerance?

A

when a drug induces its own metabolism

32
Q

In what ways can CYP450 be inhibited?

A

competitive or non-competitive

33
Q

What can cause inhibition of CYP450?

A

drugs: cimitidine, fluconazole, fluoxetine, erthromycin

34
Q

some drugs that inhibit CYP3A4 can also inhibit…?

A

drug effluc ttransporter P-glycoprotein

35
Q

What are the general feautures of glucoronyl transferase?

A

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

36
Q

What is the mechanism of reaction of glucoronyl transferase?

A

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

37
Q

where is glucoronyl transferase located?

A

in the endoplasmic reticulum

38
Q

how is the glucoronyl trransferace induced?

A

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