Exam II: Review Questions

Question 1

prontosil is a prodrug. How is it activated to an active sulfa drug, what enzyme catalyzes the rxn?

Answer 1

phase I reduction

azo reductase

Question 2

Glucuronidation enhances excretion of drugs in urine and bile in part through action of OATPs (organic anion transporter proteins. Once excreted, how can a drug reenter the bloodstream?

Answer 2

Hydrolysis by microbial glucuronidases in gut followed by reabsorption of the aglycone.

Question 3

After an investigational new drug is administered to human volunteers during a safety study, a mercapturic acid metabolite is identified in urine. What is the significance of this discovery?

Answer 3

• The mercapturic acid was probably formed from a glutathione conjugate (Phase II metabolite)
• The glutathione conjugate was probably formed by addition of GSH to an electrophilic Phase I metabolite
• The electrophilic metabolite was probably formed by Phase I oxidation.
• The electrophilic metabolite is cause for concern and should be investigated for possible toxicity

Question 4

Sulfotransferases transfer a sulfonate group from PAPs to a variety of functional groups on drug molecules. Which of the following functional groups on drugs often form sulfonated metabolites?

Answer 4

Phenols, primary and secondary alcohols

Question 5

Salicyluric acid is a major metabolite of aspirin that is excreted in urine. After aspirin is de-esterified to salicylic acid, how is salicyluric acid formed?

Answer 5

The carboxylic acid of salicylic acid is activated to an acyl-CoA complex and then conjugated with glycine by N-acyltransferase

Question 6

what is an example of a drug methylated by COMT?

Answer 6

rimiterol

Question 7

Which of the following enzymes are known to have clinically relevant polymorphisms that affect drug pharmacokinetics in some individuals?

Answer 7

CYP2C9, CYP2D6, NAT2, and alcohol dehydrogenase

Question 8

The antibiotics clarithromycin and erythromycin are potent inhibitors of CYP3A4 and can cause pharmacokinetic drug interactions with
simvastatin. Why?

Answer 8

Metabolized by CYP3A4, simvastatin blood levels will increase if CYP3A4 is inhibited

Question 9

Glutathione-S-transferases catalyze conjugation of what kinds of substrates with
glutathione?

Answer 9

Electrophiles such as epoxides and quinones

Question 10

what are the differentiating structures found in glutathione? is it an electrophile or a nucleophile?

Answer 10

sulfhydryl and primary amines. it is a nucleophile

Question 11

what is a nucleophile? relevancy to phase II enzymes?

Answer 11

something that donates electrons

phase II enzymes are typically nucleophiles since they donate electrons to a drug

Question 12

what is an electrophile?

Answer 12

forms bonds with nucleophiles by accepting electron pairs

Question 13

Excreted in urine, mercapturic acids are derivatives of what kind of Phase II metabolite?

Answer 13

Glutathione

Question 14

All of the following features distinguish Phase II reactions from Phase I reactions
except one. Which is not characteristic of Phase II reactions?
a. Phase II reactions involve radical intermediates
b. Phase II reactions are generally faster than Phase I reactions
c. Phase II reactions involve co-substrates
d. Phase II reactions are concerted reactions involving a nucleophile, an electrophile, and a leaving group

Answer 14

a. phase II reactions do not involve radical intermediates

Question 15

T/F Enzymatic ester hydrolysis is a hydrolytic reaction.

Answer 15

True

Question 16

After caffeine is demethylated by cytochromes P450 to form 1-methylxanthine, what enzyme catalyzes its transformation to 1-methyluric acid?

Answer 16

Xanthine Oxidase

Question 17

Ethanol is converted to acetaldehyde by alcohol dehydrogenase. What other enzyme catalyzes this transformation?

Answer 17

CYP2E1

Question 18

Which Phase I enzyme catalyzes the oxidative deamination of β-arylethyl amines such as norepinephrine, dopamine, serotonin, and tyramine?

Answer 18

Monoamine oxidase

Question 19

The transformation of itopride to itopride N-oxide is catalyzed by which Phase I enzyme?

Answer 19

Flavin-containing monooxygenase (FMO)

Question 20

Induction of certain cytochrome P450 enzymes and UDP-glucuronosyltransferases by drug A can cause pharmacokinetic interactions with drug B that is a substrate for these induced drug metabolizing enzymes. What is a probable consequence of this interaction?

Answer 20

The maximum plasma concentration of drug B will be reduced, the area under the curve of drug B concentration vs. time will be reduced, and the efficacy of drug B will be reduced.

Question 21

Phase II drug metabolism usually deactivates drugs and Phase I drug metabolites rendering them less pharmacologically active and less toxic. Which of the following is an example of Phase II activation of a drug to an electrophilic metabolite?
a. Glucuronidation of desipramine to an N-linked glucuronide
b. Glucuronidaton of acetaminophen to a phenol-linked glucuronide
c. Glucuronidation of ibuprofen to an acyl-linked glucuronide
d. Glucuronidation of chloramphenicol to an ether-linked glucuronide
Explain your answer!

Answer 21

C,
N-linked glucuronide is not electrophilic
phenol-linked glucuronide is not electrophilic
ether-linked glucuronide is not electrophilic
acyl-linked glucuronide is electrophilic -> glucuronidation conjugation links to a carboxylic acid which are electrophilic by nature

Question 22

Grapefruit and grapefruit juice contain furanocoumarin compounds that can cause drug interactions. Which of the following statements most accurately
describes these interactions?

Answer 22

Irreversibly inhibit CYP3A4 and OATPs (organic anion transporter polypeptides)

Question 23

Metabolism of digitalis to pharmacologically inactive dihydrodigoxin by microbial cardiac glycoside reductase-2 is an example of a drug-gut microbiome

interaction. Which of the following is true for such drug-gut microbiome interactions?
a. All patients demonstrate the same drug-gut microbiome interactions
b. Only Phase I drug metabolism interactions occur with the gut microbiome
c. Only Phase II drug metabolism interactions occur with the gut microbiome
d. The microbiome of many patients often lacks the microorganism(s) capable of producing a specific drug interaction

Answer 23

d, The microbiome of many patients often lacks the microorganism(s) capable of producing a specific drug interaction

Question 24

Explain why this is a false statement:
Inhibition of drug metabolizing enzymes is usually mediated through activation of nuclear receptors like aryl hydrocarbon receptor (AhR), pregnane X receptor
(PXR), and constitutive androstane receptor.

Answer 24

Because AhR, PXR, and constitutive androstane receptors activate to mediate the INDUCTION of drug metabolizing enzymes

Question 25

Which of the following enzymes are known to have clinically relevant polymorphisms that affect drug pharmacokinetics in some individuals?

a. CYP2C9, CYP2D6, NAT2, and alcohol dehydrogenase
b. CYP3A4 and NAT1
c. All of these enzymes
d. None of these enzymes

Answer 25

a, CYP2C9, CYP2D6, NAT2, and alcohol dehydrogenase