Introduction to Biotransformation, Pharmacogenetics and Clinical Drug Trials

Question 1

The process of making compounds into more polar, and sometimes larger, derivatives is known as which process?

Answer 1

Biotransformation

Question 2

An inactive drug that undergoes biotransformation to become an active drug is known as a __________ .

Answer 2

Prodrug

Question 3

Describe the first pass effect.

Answer 3

All drugs that are absorbed through the intestine must pass through the liver via the portal circulation first!

Question 4

Which phase in drug metabolism results in the biological inactivation of a drug?

Answer 4

Phase 1

Question 5

Which phase in drug metabolism produces a metabolite with improved water solubility and increased molecular weight? (Enhances Elimination)

Answer 5

Phase 2

Question 6

Which phases in drug metabolism are said to be catabolic vs. anabolic?

Answer 6

Phase 1 - Catabolic

Phase 2 - Anabolic

Question 7

Which phase enzymes are located in the lipophilic ER membranes of the liver?

Answer 7

Phase 1

Question 8

Which phase has oxidation, reduction, and hydrolysis reactions?

Answer 8

Phase 1

Question 9

Which phase has products that are generally more reactive and may be more toxic than the parent drug?

Answer 9

Phase 1

Question 10

What is the MAIN enzyme used in Phase 1 reactions?

Answer 10

CYP3A4 (used 50% of the time)

Question 11

What are the main enzymes used in Phase 2 reactions?

Answer 11

Transferases

UDP-glucuronosyltransferase, sulfotransferase, N-acetyltransferase

Question 12

Succinylcholine is used for quick paralysis of muscle tissue. If a patient has a polymorphism within the body that metabolizes the succinylcholine at a slower rate, what would happen with the patient?

Answer 12

The Drug would stay longer in the body

You would have to use the Bag Valve Mask for an extended period of time due to the inhibitory effects of Succinylcholine on the diaphragm

Question 13

What happens if you have a slow acetylator phenotype for N-acetyltransferase enzyme?

Answer 13

That is responsible for caffeine metabolism.

If you have a slow transferase, that means it will take a longer time for you to complete phase 2 reactions and eliminate the drug from the body!

People with slow acetylator phenotypes will only be able to drink one cup of coffee, making them wired for an entire day!

Question 14

Phenobarbital, Chronic ethanol, Aromatic hydrocarbons (benzopyrene aka tobacco smoke), rifampin and St. John’s wort are all examples of __________ .

Answer 14

Enzyme Inducers

Question 15

Grapefruit juice is an example of ________ .

Answer 15

Enzyme Inhibitor (Inhibits CYP450 enzymes)

Question 16

When acetaminophen exceeds therapeutic doses, Glucuronidation and sulfation pathways are saturated which will deplete the substrates necessary for conjugation during Phase 2 reactions. What do you use to treat Acetaminophen-Induced hepatotoxicity?

Answer 16

N acetylcysteine

Question 17

The study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy and toxicity at the genomic level.

Answer 17

Pharmacogenetics

Question 18

The study of the entire genome to assess multigenetic determinants of a drug response.

Answer 18

Pharmacogenomics

Question 19

A variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population.

Answer 19

Polymorphism

Question 20

If you have polymophisms in CYP450 and it results in a decrease in enzymatic activity, what are you at risk for?

Answer 20

Poor metabolizers are at risk for ACCUMULATION of toxic drug levels

Question 21

If you have polymophisms in CYP450 and it results in a increase in enzymatic activity, what are you at risk for?

Answer 21

Ultrafast metaolizers are at risk for being undertreated with inadequate doses

Question 22

What happens if you have polymorphisms in the Phase 2 enzymes that slow them down?

Answer 22

It will take the body longer to eliminate the drugs!

Question 23

Which drug classically has polymorphisms in biotransforming enzymes AND in the drug targer?

Answer 23

Warfarin (Coumadin)

Question 24

___________ deficiency causes oxidative damage that leads to hemolytic anemia in the presence of oxidants.

Answer 24

Glucose-6-phosphate dehydrogenase

Polymorphism in Pharmacodynamics

Question 25

____________ mutations lead to an elevation of calcium in the sarcoplasm of muscle which leads to muscle rigidity, elevation of body temperature and rhadomyolosis.

These mutations are mainly seen with the use of what drug?

Answer 25

Ryanodine Receptor Mutations

Succinylcholine (inhalational anesthetics)

(Example of mutation in Pharmacodynamics)

Question 26

Which phase of a clinical drug trial is making sure the drug doesn’t kill anyone and looking at the pharmacokinetics/safety of the drug?

Answer 26

Phase 1

Question 27

Which phase of the clinical drug trial is answering the question,” Does it Work?” and has 100-200 patients?

Answer 27

Phase 2

Question 28

Which phase of the clinical drug trial is giving the drug to the Patient, typically in a double blind study, and using a population of 1000-6000 Patients?

Answer 28

Phase 3

Question 29

Which phase of the clinical drug trial is responsible for postmarketing surveillance?

Answer 29

Phase 4

Question 30

How long does it take to get from the beginning to phase 4?

Answer 30

8-9 Years

Question 31

What is the term at which the maximum does at which a specified toxic effect is not seen?

Answer 31

No-effect dose

Question 32

What is the term for the smallest dose that is observed to kill any experimental animal under a defined set of conditions?

Answer 32

Minimum Lethal Dose (LDmin)

Question 33

What is the term for the dose that kills approximately 50% of the animals?

Answer 33

Median Lethal Dose (LD50)

Question 34

Whose job is it to assure that appropriate steps are taken to protect the rights, safety and welfare of humans participating as subject in the research?

Answer 34

Institutional Review Board (Aka Independent Ethics Committee (IEC) or Ethical Review Board (ERB))

Question 35

Why are endpoints so important to monitor?

Answer 35

There was an example of drugs used for hyperlipidemia (Vytorin). The end point monitored a decrease in LDL levels, which the drug did significantly better than placebo. However, the actual goal was to DECREASE major cardiovascular events in which the drug and placebo were equals.

Question 36

Ryanodine receptor mutations and Glucose-6-Phosphate Dehydrogenase deficiency are examples of _____________ .

Answer 36

Variations in Pharmacodynamic Response

Question 37

Polymorphisms in CYP450 and Transferases are examples of ______________ .

Answer 37

Variations in Pharmacokinetic Response

Question 38

A variation in the rate at which the body absorbs, transports, metabolizes or excretes a drug/metabolite is a variation in __________ .

Answer 38

Pharmacokinetics

Question 39

An allelic variation in a drug’s downstream targets, such as receptors, enzymes, or metabolic pathways is a variation in __________ .

Answer 39

Pharmacodynamics