Metabolism and Biotransformation Lect 7 Flashcards Preview

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Flashcards in Metabolism and Biotransformation Lect 7 Deck (45):
1

most pharmacologically active drugs have what qualities at physiological pH

  • lipid soluble
  • non-ionized
  • strongly bound to plasma proteins and other tissues 

2

what is the biotransofrmation of drugs

converts lipid-solube, non-ionized compounds to water-soluble, ionized metabolites

3

where are most drugs metoblized 

liver

* some occurs in GI tract

4

what molecular weight classifications determines if a drug is excreted by the kidney or in bile

  • MW < 350 is excreted by kidney
  • MW > 350 is excreted in bile 

5

give an example of a drug that must be metabolized to be active 

codeine (prodrug) -> morphine (active metabolite)

6

Name a drug in which its metabolites are more active than the parent drug

Diazepam (active drug) -> Nordiazepam -> Oxazepam (both active metabolites) 

7

Name a drug that is metabolized to toxic metabolites 

acetaminophen (active drug) -> N-acetyl-p-benzoquinone imine (toxic metabolite) 

8

What happens during phase I of biotransformation reactions

modification of molecule

  • converts lipid-soluble, non-ionized compounds to more ionized, hydrophilic metabolites
    • some metabolites are inactive and readily excreted
    • other metabolites may undergo phase II conjugation 

9

what happens during phase II biotransformation reactions

conjugation

  • adds an ionized, charged particle (peptide, protein) to a phase I metabolite to form a more polar and hydrophilic conjugate 

10

in some cases, phase II (conjugation) occurs before phase I (modification). Give an example

isoniazid

  • acetylation (II) followed by hydrolysis (I)
  • results in toxic metabolites
  • high degree of genetic polymorphisms 

11

what are the most common phase I reactions

oxidation

12

characteristics of phase I reactions

  1. not compound specific
  2. no specific enzymes metabolizing a particular drug
  3. enzymes attack functional groups or bonds of multiple drugs
  4. introduce or "unmask" chemical functional groups (OH, SH, NH2)

13

example of phase I reaction of a molcule that contains a benzene ring

  • benzene ring can be hydroxylated (adding OH group)
  • or an O-CH3 group can be de-methylated 

14

what are cytochrome P450s (CPY450). What are their functions?

family of microsomal enzymes in the liver

  • function: oxidation (formation of OH) of mulitple drugs; acts as a handle for phase II conjugation 

 

15

function of CYP450 subtype CYP3A4

metabolizes >50% drugs

* drugs metabolized by 3A4 have high degree of drug interactions

16

function of CYP450 subtype CYP2D6

polymorphism impairs codeine metabolism 

17

function of CYP450 subtype CYP2E1

metbolizes, and is induced by alcohol

18

all phase I microsomal enzymes (CYP450s) are inducible except which one

2D6

19

which is the only phase II enzyme which is microsomal and inducible

glucuronyl transferase 

20

enzyme induction or inhibition can increase drug toxicity. In light of this, why do you not want to consume alcohol while taking acetaminophen?

ethanol induced CYP2E1 increasing acetaminophen metabolism and potential hepatotoxicity caused by metabolites 

21

smoking and chargrilled foods induces what CYP enzyme

1A2

22

barbituates/phenobarbital, and St. John's wort induce what CYP enzymes

  • 2A6
  • 2B6
  • 2C8
  • 2C9
  • 2C18
  • 3A4

23

ehtanol induces what CYP enzyme

2E1

24

grapefruit juice inhibits what CYP enzyme

3A4

25

Quinidine inhibits what CYP enzyme

2D6

26

function of monoamine oxidase (mitochondrial)

inactivates amines

27

warfarin is inactivated by a reduction reaction (adding H+) by what CYP enzyme

CYP2A6

28

hydrolytic reactions occur in plasma and in many tisues. Esterases and amidases are metabolized in this fashion by what enzyme

psuedocholinesterase 

29

Esterases, amidases, alcohol dehydrogenase, and monoamine oxidase these enzymes are involved in CYP450 independent oxidative reactions.  What does this mean

these enzymes are not inducible 

30

where does the majority of phase II reactions (conjugation) occur. What are they mediated by

  • liver
  • glucuronidation and UGT (UDP glucuronyl transferase)

31

characteristics of end products of phase II reactions

  • decreased lipid solubility
  • polar and inactive
  • have a large molecular weight 
  • readily eliminated 

32

most common phase II conjugation

functional groups (OH, SH, NH2) conjugated with glucuronic acid

  • glucuronic acid is transferred to the substrate, forming a bond via UGT (UDP glucuronyl transferase) 

** biliruben and adrenal corticosteroids are conjugated by this system

33

sulfonamides, isoniazid, clonazepam, dapsone, and mescaline undergo what type of conjugation

acetylation 

34

CYP2D6 has a large degree of polymorphisms: inhertied autosomal recessive trait. what is usually affected 

  • leads to poor metabolism of codeine to morphine 

35

 why does alcohol flush reaction occur

a condition found in Asian populations in which the face and/or body experiences flushes after consuming alcohol. Caused by the accumulation of acetaldehyde due to a polymorphism that encodes the enzyme, acetaldehyde dehydrogenase which metabolizes acetaldehyde, a toxic product of the alcohol metabolism

36

acetaminophen metablism can form toxic metabolites in chronic drinkers 

  • acetminophen is a GSH (glutathione)-conjugated metabolite
  • increased production of free radicals may exhaust the supply and free radical molecules can then induce toxicity (oxidative stress)

37

describe "Freeing" of drugs in enterohepatic circulation

  • The compounds secreted into the bile following liver metabolism are not always excreted but often go through the enterohepatic cycle and are reabsorbed
  • Some glucuronides that are secreted into the bile are cleaved by glucuronidases in the small intestine, “freeing” the parent drug for reabsorption. (conjugate is removed and drug is freed)

A image thumb
38

what happens to half life of drugs that enter enterohepatic circulation

long half life 

39

excretion of drugs is enhanced by what

  • agents that bind drugs in the intestive (charcoal) increasing peristalsis
  • antibiotics that eliminate GI bacteria 

40

how does young age influence metabolism 

  • organ maturation is incomplete
    • blood brain barrier is not fully developed
    • liver function and renal excretion is not developed

41

how does being elderly influence metabolism

  • decreased renal function occurs first
  • decreased hepatic metabolism
  • slower gastric emptying and decreased gastric secretion

42

how does liver cancer modify drug metabolism

patients have lower CYP450 enzymes resulting in slow metabolism of many drugs 

43

drugs differ in the rate at which they are excreted by the kidney. How do penicillin and diazepam differ.

  • PCN: cleared almost completely of a single transit through the kidney
  • Diazepam: is cleared very slowly. 

44

which is excreted more quickly: products of phase I and II metabolism or parent compound

products of phase I and II metabolism

45

what are the 3 basic processes that accoun for differences in renal excretion

  1. glomerular filtration
  2. active tubular secretion or reabsorption
  3. passive diffusion across tubular epithelium