Drug Metabolism Pt 6: Notes

Question 1

Drug metabolism can be used to ______________.

This is important because _______ at renal absorption and renal excretion than
_______. A lipophilic drug can be made hydrophilic by:

CH3 -> CH2OH -> ? ->COOH.

Answer 1

convert lipophilic drugs to hydrophilic drugs

hydrophilic drugs are better

lipophilic drugs

? = CHO

Question 2

Metabolism is done for ____.

Answer 2

termination of drug action

Question 3

Drug action can be terminated by:

a. ?- An active drug can be altered so that it becomes inactive.
b. ?- a drug has a toxic effect can be changed into a product with non-toxic
properties.
c. ?- drug action can be terminated by making it more water soluble and
aiding its excretion.

Answer 3

• Bioinactivation:
  
  • E.g.: cleaving the ester bond in Procaine makes it inactive
• Detoxification:
  
  • E.g.: Antabuse (drug used to treat alcoholism- makes people sick) will be detoxified by cleaving the disulfide bond, thus terminating the drug action.
• Elimination:
  
  • E.g.: Acetaminophen is converted to Sulfate and Glucoronide,
    two water soluble compounds, and excreted.

Question 4

Metabolism is done for _____, which is converting the drug to active forms.

Answer 4

bioactivation of drugs

Question 5

The three ways of bioactivation of drugs are:

Supply term and definition

a. ??????: ____________. E.g.: Imipramine -> Despiramine.
b. ??????: ____________. E.g.: Sulfindac -> Sulfindac sulfate

c. ??????: ____________. E.g.: MPTP -> MPDP -> MPP+ (TOXIC)

Answer 5

• a. Active metabolites: This happens by chance- the drug is NOT designed to convert itself to active metabolites. The parent drug is converted to an active form that is very similar to the parent drug.
• b. Prodrugs: Prodrugs are designed to be precursors to the active form of the drug. This is done for better absorption at different parts of the body. E.g.: if we want a drug to act in the brain, the pro drug would be made lipophilic so that it can pass the blood brain barrier. The pro drug would then be converted to the active hydrophilic form of the drug to aid absorption and excretion.
• c. Toxification: This happens on accident, when a metabolite would get converted to its toxic form by metabolism in the body.

Question 6

Metabolism should be studied to know about drug interactions.

Give 2 examples:

Answer 6

1. Warfarin, an anticoagulant, is converted to its inactive metabolite by P450.
   Chloramphenicol, an antibiotic, inactivates P450, so warfarin gets accumulated and causes bleeding. So, for a patient on warfarin, we should use another antibiotic OR adjust the dosage of warfarin accordingly (low when given with chloramphenicol, increase when chloramphenicol is stopped).
2. imuran -> mercaptopurine (active form) -> changed by xanthene oxidase to
   thiouric acid and excreted.Allopurinol, used to treat gout, blocks xanthene oxidase, thus accumulating Mercaptourine in the body and causing bone marrow suppression. People on Imuran should be prescribed a different treatment for gout.

Question 7

Explain:

Stereochemical implications of drug metabolism

Answer 7

Some drugs are a racemic mixture of two enantiomeric forms of the drug- R & S. Usually the S form is the active form. Our body can automatically convert between the enantiomers. It does so in S & R Ibuprofen. However, in some cases, the body can’t interconvert.

• E.g.: in the elderly, the R form of Benaxoprofen (Oraflex) can’t be inter-converted and this leads to accumulation of the toxic R form.

Question 8

By studying metabolism, we can predict metabolic pathways. This will help us to:

Answer 8

• avoid toxigenic pathways
  o Analyze cytotoxicitiy (harmful to cells), carcinogenicity (cancer causing),
  mutagenecity (mutation inducing)
  o Risk assessment in new drug development
  o Avoid toxic pathways in long term therapy vs. acute therapy
• Speed up metabolism: e.g.: pain killers used in fillings. We want these to wear off as soon as possible
• Slow down metabolism: e.g.: we don’t want anesthetics used for root canal procedures to wear off too quickly

Question 9

Study of metabolism is required by FDA because it affects

Answer 9

efficacy and toxicity.

Question 10

Phase 1 metabolism: it is done to enhance excretion or prepare the drug for phase 2
metabolism. it is known as functionalization reactions because it involves:

Answer 10

o Introducing new polar functional groups.

E.g. oxidations (hydroxylation) RH -> ROH

o Interchanging existing functional groups to make it more polar.

E.g. reductions: C=O -> CH-OH

o Unmasking existing polar groups that lay within the molecule to make the
molecule more polar.

E.g. hydrolyses RCO2CH3 -> RCOOH + CH2OH

Question 11

Phase 2 metabolism: these reactions act on the parent drug or the phase I metabolite. It is known as “conjugation” reactions because it links molecules (endogenous, polarizable, ionizable groups) to non-polar molecules to make the metabolite more polar. This helps in enhancing excretion.

Types of reaction

Answer 11

o Glucuronidation
o Sulfate formation
Phase I and Phase 2 compliment each other- they are not mutually exclusive. Depending on the polarity of the drug, it gets excreted when it is most polar.

Question 12

Liver:

o The liver metabolizes major xenobiotic compounds (plant toxins, foreign
compounds) and endobiotic compounds (endogenous compounds, steroids, heme,
compounds that exist in the stomach).

What else does it do?

Answer 12

o Presystemic first pass effect: The liver is located on top of the stomach so that
substances can be detoxified before it goes into circulation. The first pass effect
also happens in the GI mucosa during absorption.
o in regular drugs, first pass effect might metabolize all of the drug or just part of it.
To overcome the first pass effect, we can:

• administer drug in another site: buccal, transdermal, nasal
• chemistry: make drug harder to metabolize by liver
• increase doses
• administer multiple doses
• use prodrugs

*prodrugs: changing the inactive forms of the drug to active forms in the body. Changing prodrugs to active forms involves ester hydrolysis.

Question 13

Gut tract: the _____ is very rich in drug metabolizing enzymes for Phase 1 and Phase 2 metabolism. It is significant for ____

Answer 13

epithelium

oral bioavailability

Question 14

Gut flora: the gut flora does:

Answer 14

o Reduction: changing a drug to the active form- mostly localized
o Deconjugated: drug is conjugated with sugar that is digested by the gut flora to expose the drug
o Endobiotic: the conjugation of drug is so big that the liver can’t metabolize it so it goes to bile.

Question 15

Kidneys, lungs, brain: for

Answer 15

Kidneys, lungs, brain: for localized bioactivity and toxicity

Question 16

PHASE I OXIDATIONS: P 450

• Physical properties: they are heme enzymes. They are an enzyme family of ____________they have different physical properties).
• They bind CO2 at 450nm
• They have a _____non specific substrate
• They are slow because a given drug molecule is competitively inhibited by other molecules, and this can lead to toxicity due to accommodation
• Overall reaction:
  
  • RH + _____
• Mono-oxygenase: one oxygen atom ends up in the product

Answer 16

• about 50 isoforms (the members of this family are not identical-
• broad metabolic specificity:
• RH + NADPH + H+ + O2 -> ROH + NADP + H2O

Question 17

450 Cycle: the substrate enters as RH- goes through the cycle until it comes to an active oxygen in the end and it gets oxidized to ROH.
• The active oxygen species attaches to the heme center and is electron deficient and highly electrophilic. So it bonds with the substrate on the P450
• Mechanism:???

Answer 17

Mechanism: The enzyme is just involved in the first step, where it places an arene oxide on the substrate. The arene oxide destroys aromaticity and creates an “unstable” epoxide. A NIH shift takes place (H moves from para to meta position), a carbonyl is formed (at the para position) which is changed to a hydroxyl to restore aromaticity (refer slide on page 4). The para position is preferred due to resonance (the para position gives 4 different resonance structures, whereas the meta position gives 3 resonance structures).

Question 18

Possible fate of arene oxides:
1-3

Answer 18

1. Rearrange to phenol: this will lead to bioactivation, detoxification, or excretion depending on the drug
2. Reaction with glutathione (GSH): [enzyme: glutathione S- transferase]: arene oxides react with GSH for detoxification. GSH attacks at the para position (SN2) and water is removed to get SG at the para position. This detoxifies the drug and
   helps in excretion
3. Reaction with water [enzyme: epoxide hydratase]: water attacks SN2 as a nucleophile and gives rise to trans-dihydrodiol (change stereochemistry at para
   position where H2O attacks). This detoxifies the drug and helps in excretion

Question 19

Aromatic hydroxylation happens on ___ aromatic rings and the position of hydroxylation depends on rules of ______ (activating: ortho/para directors). So when ____ is placed on a ring, it is deactivation so the drug will not hydroxylate.

Answer 19

• activated
• electrophilic aromatic substitution
• a halogen

Question 20

Aromatic hydroxylation

• Activating groups: ???
• Deactivating groups: ???
  
  • Aromatic hydroxylation does not happen here.

Answer 20

• Activating groups:
  
  • NH2, OH, NHCOCH3, NHCOR, OCH3, OR,
  • CH3, C2H5, R, C6H5
• Deactivating groups:
  
  • NO2,NR3,CF3, CCl3 CN, SO3H, CO2H, COH,
  • F, CL, BR, I.

Question 21

Stearic hindrance is not an issue in aromatic hydroxylation because the P450 attacks the pi electrons that are not in the plane of the hindering molecules.
• ______ can also happen when there are no groups on the ring.

Answer 21

Aromatic hydroxylation

Question 22

Alkene epoxidation

alkene -> ??-> trans-diol

Answer 22

epoxide

Question 23

Benzylic hydroxylation:
• Benzylic carbon: aliphatic carbon (sp3) that is directly next to any aromatic carbon.
• CH3 -> CH2OH
• Further stabilizations are ______

Answer 23

• possible by alcohol dehydrogenase and aldehyde dehydrogenase

Question 24

W and w-1 hydroxylation
• In w hydroxylation, ______ gets hydroxylated to

OH - > CHO - > COOH
• In w- 1 hydroxylation, the carbon only goes to a 3rt alcohol.

Answer 24

• the terminal carbon

Question 25

Heteroatom dealkylation

Heteroatoms :?????

Aliphatic carbons attached to heteroatoms can be deaalkylated to get a H attached to the heteroatom. An OH group attacks such carbons and then the aliphatic carbon is converted
to aldehyde and it leaves the heteroatom attached to a H.

Answer 25

Heteroatoms : N,S, O

Question 26

Oxidative deamination

• The aliphatic carbon next to the heteroatom (e.g. NH2) gets an OH attached on there. The H leaves forming a =O kicking out the heteroatom.
• This reaction is done on xenobiotics (substances foreign to the body).
• ________amines is done NOT by P450 but by MAO. It is a different mechanism but it gives the same product.

NH2 -> =NH -> =O

Answer 26

• Oxidative deamination in endogenous

Question 27

Heteroatom oxidation

Answer 27

This is oxidation using the heteroatom’s lone pair(e.g. R-N-(CH3)2 ) of electrons that grabs an O.

Oxidation follows the rule of basicity, which is the availability of the lone pair electrons.
o Amines are more basic than amides because in amides, delocalization of the lone pairs happen.
o In pyridine, pyrrole, indole, the N lone pair is within the ring so it is not basic.
• Heteroatom oxidation can also happen with S where both the lone pairs will be oxidized.
So sulfide -> sulfoxide -> sulfone
• Primary and secondary amines form hydroxyl amines. Tertiary amines form amine oxides.