8-7 Drug Metabolism

Question 1

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Answer 1

A: Drugs are often metabolized into INACTIVE, water-soluble compounds when they undergo biotransformation. This is good because water-soluble compounds are more easily eliminated from the body.
-This occurs during Phase 1 and Phase 2 when the drug has a functional group added and is conjugated.

A2: Biotransformation(metabolism) can also seldomly ACTIVATE a drug.

Question 2

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Answer 2

A: Phase 1 enzymes are located on the [Endoplasmic Reticulum] and Add/or unmask functional groups on lipophilic drugs = functionalization = more polar

A2: There are 4 Main Phase 1 Reactions:

1) Microsomal Oxidation (i.e. hydroxylation rxn = OH functional group is introduced)
2) Reduction
3) NON-Microsomal Oxidation (alcohol oxidation)
4) Hydrolyses

Question 3

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Answer 3

B: Phase 2 enzymes are located in Cytoplasm of Hepatocytes and add endogenous conjugates to the functional groups added during Phase 1

Question 4

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Answer 4

A: Phase 1 Microsomal Oxidation (adding hydroxyl group to the drug substance) is catalyzed by the [Mixed Functional Oxidases - monooxyganses] enzymes on the Smooth ER.

NADPH takes an O2 and adds an O to the [RH drug compound] and to a single H+ atom—> [ROH drug compound] + OH. It then donates its H+ atom to the OH —> H2O + [ROH drug compound]

Question 5

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Answer 5

A: MOST EtOH is metabolized by [Cytosolic Alcohol Dehydrogenase] into [DANGEROUS ACETALDEHYDE]. This [DANGEROUS ACETALDEHYDE] typically finds its way to the mitochondria where the enzyme there (Acetaldehyde Dehydrogenase) can —> Acetate

A2: some EtOH is metabolized by the [Smooth ER CYP2E1]

Question 6

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Answer 6

A: Via Hydrolysis Rxn: Procaine is hydrolyzed into PABA (ParaAmino Benzoic Acid) and this has structural similar to Sulfanilamides! This means Sulfanilamides may lose its therapeutic effects as an abx if PABA from Procaine or Procainamide competes for the same bacterial inhibitory sites.

Question 7

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Answer 7

Difference between [Pharmacokinetic Tolerance] and [PharmacoDynamic Tolerance]

[Pharmacokinetic Tolerance]= 1 Drug induces an enzyme and that enzyme actually induces the metabolism of a co-administered drug–>Reduces efficacy of 2nd drug!

vs.

[PharmacoDynamic Tolerance] = Slow Desensitization of a drug to a receptor due to down-regulation of receptors, enzymes and ion channels

Question 8

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Answer 8

A: Phenobarbital specifically has the ability to INDUCE the INC expression of CYP2B from the liver.

B: Grapefruit Juice actually BLOCKS [Microsomal CYP3A4] —> [Potential Drug OD] as this enzyme metabolizes 50% of drugs!

C: Cimetidine competitively binds to [Cytochrome P450] enzymes and REVERSIBLY BLOCKS IT

D: SPIRANOLACTONE NON-COMPETITIVELY binds to [Cytochrome P450] enzymes and NON-REVERSIBLY BLOCKS IT!

Question 9

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Answer 9

A: SNP (Single Nucleotide Polymorphism) = alteration in 1 nucleotide of the DNA that can occur in either the coding region (will change amino acid production) OR NON-coding region (will change promoters/enhancers/splicing sites)

B: Poor metabolizers (those who likely have Inhibiting polymorphisms) will require LOW maintenance dosing because more active drug remains in plasma longer

C: Ultrarapid metabolizers (those with ACTIVATING POLYMORPHISMS) require HIGH maintenance dosing

D: Polymorphisms often affect Drug efficacy vs. toxicity most when they occur in the [Drug metabolizing enzymes] or [Receptors] at which drugs act

Question 10

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Answer 10

Phase II enzymes NAT1 and NAT2 = Only Known Acetylation Enzymes.

A: [NAT1 and NAT2] reside in cytoplasm and takes acetate (from Acetyl-CoEnzyme A) and places it on either

• aromatic amines
• hydrazine

B: Acetylation is necessary to reduce carcinogenic exposure but DOES make some compounds less soluble in urine —> crystalluria

C: Acetylation is also needed for Sulfanilamides (reduces hypersensitivity) / Hydralazine (prevents lupus onset) / prevents peripheral neuropathy

D: 50% of the Caucasian population have a slow Acetylation/ Conjugation phenotype secondary to polymorphisms in NAT2

E: Hydralazine also (for some reason) works really well in African Americans but causes Excess Vitamin B6 Excretion and potential Niacin deficiency–> Potential Pellagra!

Question 11

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Answer 11

[Phase 1 enzyme - CYP2D6 metabolizes TBAN]

• Tri-cyclic Antidepressants
• Beta blockers
• Anti-arrhrythmics
• Neuroleptics

Question 12

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Answer 12

Warfarin is metabolized by [Phase 1 - CYP2C9] which is a polymorphic drug enzyme. It accounts for 10% of Warfarin Variability.

B: 25% of Warfarin Variability is due to mutation in [VKORC1]. Warfarin normally prevents [VKORC1] from utilizing Vitamin K to make clots. If [VKORC1] has a mutation in its pharmacophore, then Warfarin will be unable to act on it! —> PharmacoDynamic Variability

C: [Phase 1 - CYP2C9] also carries an INEFFECTIVE ALLELE in 40% of Caucasians. This is bad because [Phase 1 - CYP2C9] metabolizes Warfarin / NSAIDs / Phenytoin

Question 13

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Answer 13

B: Another example is HERCEPTIN. Herceptin is a VERY SPECIFIC humanized monoclonal antibody drug that binds to the [Human Epidermal growth factor Receptor - 2] on tumor surfaces. The [HER2 - Receptor Tyrosine Kinase] allows tumors to grow uncontrollably.
-[HER2] is genetically amplified sometimes and this leads to overexertion on cells —> neoplasia. This can be detected using FISH [Fluorescent in-situ hybridization]

Question 14

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Answer 14

[CML - Chronic Myelogenous Leukemia] occurs when the mid-portion of Chromosome 22 translocates to Chromosome 9. This allows the [Bcr gene near the top of Chromo 22] and the [Abl gene near the bottom of Chromo 22] to come together and form a fused gene/protein = [Philadelphia Chromosome] —-> [Bcr-Abl Receptor Tyrosine Kinase] protein development

B: [Bcr-Abl Receptor Tyrosine Kinase] is a constitutively active growth receptor located on leukocytes–> neoplasia.

C: Gleevec is a pharmacogenomically developed drug that specifically targets [Bcr-Abl Receptor Tyrosine Kinase] and slows progression.