Factors Affecting Drug Response

Question 1

What are the requirements for drugs to be excreted renally (kidney)?

Answer 1

molecular weight <300

Question 2

How does the pH of the distal tubular affect the excretion of drugs?

Answer 2

the distal tubular is generally acidic (pH < 7) and ionized compounds have enhanced urine excretion

Question 3

What are the requirements for drugs to be excreted via bile?

Answer 3

hydrophilic, molecular weight >500, nonpolar compounds <300=not excreted in bile

Question 4

Describe: Enterohepatic Recycling

Answer 4

liver actively secretes drugs and metabolites into the bile -> bile is released into the small intestine -> drugs and metabolites are re-absorbed from the intestine through the portal vein back into the liver

Question 5

How can enterohepatic recycling affect drug excretion and bioavaliability?

Answer 5

gut microorganisms (flora) can mediate biotransformations of drugs and metabolites= decarboxylation, dehydroxylation, dealkylation, deamination, glucuronidation. this can result in reabsorption into portal system.

Question 6

Describe how Digoxin is effected by enterohepatic recycling

Answer 6

gut flora metabolizes digoxin to more polar metabolite to facilitate fecal excretion

Question 7

Describe how oral contraceptives are effected by enterohepatic recycling

Answer 7

oral contraceptives become glucuronidated by the liver, but gut gut flora de-glucuronidated the drug back to the parent drug

Question 8

In a patient taking digoxin, how would plasma concentration of digoxin change after long-term use of antibiotics, which can disrupt normal intestinal flora?

Answer 8

higher digoxin level due to decreased fecal excretion

Question 9

If normal intestinal flora is disrupted by antibiotics, how would the plasma concentration and bioavailability of oral contraceptive drugs change?

Answer 9

decreased plasma concentration, decreased bioavailability

Question 10

CYP450 2D6 enzyme is involved in phase I biotransformations, what are the substrates discussed in class?

Answer 10

-tolterodine (OAB)
-propranolol, carvedilol, nebivolol, timolol (adrenergics)
-codeine, dextromethorphan, hydrocodone, oxycodone (opioids)
-many more!

Question 11

CYP450 2D6 enzyme is involved in phase I biotransformations, what are the inhibitors discussed in class?

Answer 11

-chloroquine
-fluoxetine
-haloperidol
-imatinib

Question 12

Define: Biomarker

Answer 12

defined characteristic that is measured as an indicator of normal biological process, pathogenic processes or responses to an exposure or intervention

Question 13

Define: Diagnostic Biomarker

Answer 13

a biomarker that detects or confirm the presence of a disease or condition of interest, or identifies an individual with a subtype of the disease

Question 14

Define: Prognostic Biomarker

Answer 14

a biomarker used to identify the likelihood of a clinical event, disease recurrence, or disease progression in patients with a disease or medical condition of interest

Question 15

Define: Predictive Biomarker

Answer 15

a biomarker used to identify individuals who are more likely to experience a favorable or unfavorable effect from exposure to a medical product or environmental agent

Question 16

Define: Polymorphism

Answer 16

a genetic variant has a difference in DNA sequence compared to a reference sequence

Question 17

Define: Single-nucleotide Polymorphism (SNPs)

Answer 17

most common genetic variants, could be:
-coding nonsynonymous SNPs
-coding synonymous
-noncoding SNPs (promoter, introns, enhancers… ect)

Question 18

Define: Indels

Answer 18

insertions/deletions

Question 19

How do genetic polymorphisms affect Pharmacokinetics?

Answer 19

enzymes involved in phase I and phase II metabolism and drug transporters (affects effectiveness and possibly toxicity) and drug efflux pumps

Question 20

How do genetic polymorphisms affect Pharmacodynamics?

Answer 20

drug targets (receptos, enzymes…)

Question 21

What are the four major phenotypes of CYP2D6?

Answer 21

-2 functional alleles + multipations = ultrarapid metabolizers
-1 functional allele + 1 reduced function allele = extensive metabolizer
-1 reduced function allele + 1 nonfunctional allele = intermediate metabolizer
-2 nonfunctional allele = poor metabolizer

Question 22

For patients that are “poor metabolizers” CYP2D6 phenotypes, what drug should be used to relieve severe pain?

Answer 22

morphine

Question 23

Describe how patients who are “poor metabolizers” would respond to Tanmoxifen?

Answer 23

since it is used for the treatment of estrogen receptor-positive breast cancer and is a prodrug (becomes active metabolite in vivo)- pt who are poor metabolizers (35% of women) will not benefit from this therapy

Question 24

Describe the biotransformation of Irinotecan

Answer 24

a prodrug that is conjugated to glucuronide to create the active drug by UGT1A1

Question 25

What is Gilbert Syndrome?

Answer 25

decreased gene expression/enzyme activity of UGT1A1= defect in glucuronidation

Question 26

How can enterohepatic recycling affect toxicity of Irinotecan?

Answer 26

irinotecan (prodrug) -> SN-38 (active drug) is further glucuronidated to SN-38G to be excreted in bile. gut bacteria can de-glucuronidate SN-38G -> SN-38 but excess amounts can be toxic to the blood and gut = poor metabolizers may be more at risk for this.