Metabolism and Biotransformation Lect 7

Question 1

most pharmacologically active drugs have what qualities at physiological pH

Answer 1

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

Question 2

what is the biotransofrmation of drugs

Answer 2

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

Question 3

where are most drugs metoblized

Answer 3

liver

* some occurs in GI tract

Question 4

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

Answer 4

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

Question 5

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

Answer 5

codeine (prodrug) -> morphine (active metabolite)

Question 6

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

Answer 6

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

Question 7

Name a drug that is metabolized to toxic metabolites

Answer 7

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

Question 8

What happens during phase I of biotransformation reactions

Answer 8

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

Question 9

what happens during phase II biotransformation reactions

Answer 9

conjugation

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

Question 10

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

Answer 10

isoniazid

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

Question 11

what are the most common phase I reactions

Answer 11

oxidation

Question 12

characteristics of phase I reactions

Answer 12

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)

Question 13

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

Answer 13

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

Question 14

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

Answer 14

family of microsomal enzymes in the liver

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

Question 15

function of CYP450 subtype CYP3A4

Answer 15

metabolizes >50% drugs

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

Question 16

function of CYP450 subtype CYP2D6

Answer 16

polymorphism impairs codeine metabolism

Question 17

function of CYP450 subtype CYP2E1

Answer 17

metbolizes, and is induced by alcohol

Question 18

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

Answer 18

2D6

Question 19

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

Answer 19

glucuronyl transferase

Question 20

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

Answer 20

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

Question 21

smoking and chargrilled foods induces what CYP enzyme

Answer 21

1A2

Question 22

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

Answer 22

• 2A6
• 2B6
• 2C8
• 2C9
• 2C18
• 3A4

Question 23

ehtanol induces what CYP enzyme

Answer 23

2E1

Question 24

grapefruit juice inhibits what CYP enzyme

Answer 24

3A4

Question 25

Quinidine inhibits what CYP enzyme

Answer 25

2D6

Question 26

function of monoamine oxidase (mitochondrial)

Answer 26

inactivates amines

Question 27

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

Answer 27

CYP2A6

Question 28

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

Answer 28

psuedocholinesterase

Question 29

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

Answer 29

these enzymes are not inducible

Question 30

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

Answer 30

* liver * glucuronidation and UGT (UDP glucuronyl transferase)

Question 31

characteristics of end products of phase II reactions

Answer 31

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

Question 32

most common phase II conjugation

Answer 32

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

Question 33

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

Answer 33

acetylation

Question 34

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

Answer 34

* leads to poor metabolism of codeine to morphine

Question 35

why does alcohol flush reaction occur

Answer 35

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

Question 36

acetaminophen metablism can form toxic metabolites in chronic drinkers

Answer 36

* 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)

Question 37

describe "Freeing" of drugs in enterohepatic circulation

Answer 37

* 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)

Question 38

what happens to half life of drugs that enter enterohepatic circulation

Answer 38

long half life

Question 39

excretion of drugs is enhanced by what

Answer 39

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

Question 40

how does young age influence metabolism

Answer 40

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

Question 41

how does being elderly influence metabolism

Answer 41

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

Question 42

how does liver cancer modify drug metabolism

Answer 42

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

Question 43

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

Answer 43

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

Question 44

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

Answer 44

products of phase I and II metabolism

Question 45

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

Answer 45

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