Intro Drug Biotransformation, Pharmacogenomics, And Clinical Drug Trials-lecture + CIS-Kruse

Question 1

Acetylsalicylic acid (aspirin) –> acetic acid + salicylate

This is an example of ___

Answer 1

Inactivation

Question 2

Diazepam –> Oxazepam

This is an example of ___

Answer 2

Active compound –> active compound

-biotransformation into another active compound

Question 3

L-dopa –> dopamine

This is an example of ___

Answer 3

Activation

-prodrug- an inactive drug that undergoes biotransformation to become an active drug (L-dopa in an inactive or pro-drug)

Question 4

Where does biotransformation mostly occur?

Answer 4

In the liver at some point between absorption into the general circulation and renal elimination

Question 5

__ is the process by which oral drugs undergo extensive biotransformation after absorption prior to entering circulation

Answer 5

1st pass effect

Drugs administered parenterally do not undergo 1st pass biotransformation

Question 6

The 1st pass effect greatly limits the bioavailability of some drugs such that alternative routes of administration must be explored. List a classic example of this

Answer 6

Morphine

Ora bioavailability is roughly 25% so parenteral administration is preferred

Question 7

As a general rule:

__ result in the biological inactivation of the drug

___ produce a metabolite with improved water solubility and increased molecular weight (enhances elimination)

Answer 7

Phase 1 rxns

Phase 2 rxns

Question 8

__ consist of enzymes that convert the parent drug to a more polar metabolite

Answer 8

Phase 1 rxns

• catabolic
• phase 1 products can be more reactive and sometimes more toxic than the parent drug

Question 9

___ consist of enzymes that form a conjugate of the substrate

Answer 9

Phase 2 rxns

• conjugation with endogenous substrates to improve water solubility and increase MW
• anabolic

Question 10

Phase 1 is usually followed by phase 2. List an exception to this:

Answer 10

Isoniazid –> used for TB tx, acetylated 1st by N-acetyltransferase

Question 11

What types of rxns comprise phase 1 rxns?

Answer 11

Oxidations, reductions, and hydrolysis

-products are generally more reactive and may be more toxic than the parent drug

Question 12

Where are phase 1 enzymes located?

Answer 12

In lipophilic ER membranes of the liver (and other tissues)

Question 13

List some well-characterized enzyme-inducers:

Answer 13

Phenobarbital, chronic ethanol (higher CYP450 2E1), benzo[a]pyrene (tobacco smoke), rifampin, st johns wort

Question 14

List some well-characterized enzyme inhibitors:

Answer 14

Grapefruit juice

Compound in juice that inhibits CYP450 enzymes, that will then effect steady state dose of drug you are taking

Question 15

List ways in which acetaminophen is normally metabolized:

Answer 15

95% glucuronidation and sulfation

5% P450-dependent GSH conjugation

Question 16

Describe glucuronidation and sulfation pathways in acetaminophen toxicity:

Answer 16

They are saturated and P450 pathways become increasingly important. Over time, hepatic GSH is depleted faster than is regenerated and toxic metabolites accumulate resulting in hepatotoxicity

Question 17

__ is the study of differences in drug response d/t allelic variation in genes affecting drug metabolism, efficacy, and toxicity at the genomic level

Answer 17

Pharmacogenetics

Question 18

__ is the study of the entire genome to assess multigenetic determinants of drug response

Answer 18

Pharmacogenomics

Question 19

___ is 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

Describe drug-response variability & genetics in relation to pharmacokinetics:

Answer 20

Variation in the rate at which the body absorbs, transports, metabolizes, or excretes a drug/metabolites

Question 21

Describe drug response variability & genetics as it relates to pharmacodynamics:

Answer 21

Allelic variation in a drugs downstream targets, such as receptors, enzymes, or metabolic pathways

Question 22

Polymorphisms in CYP450s can result in absent, decreased, or increased enzyme activity. Describe poor metabolizers vs ultrafast metabolizers:

Answer 22

Poor metabolizers are at risk for accumulation of toxic drug levels

Ultrafast metabolizers are at risk for being undertreated with inadequate doses

Question 23

this enzyme deficiency is the most common disease-producing enzyme defect of humans. Deficiencies cause oxidative damage that leads to hemolytic anemia in the presence of oxidants

Answer 23

Glucose-6-phosphate DH deficiency

Question 24

What happens with adminstration of succinylcholine in an individual with a polymorphism in butyrcholinesterase?

Answer 24

Succinylcholine is a fast acting paralytic. A pt with this polymorphism will take longer to come out of a paralytic state

Question 25

Lead compounds are associated with what type of study?

Answer 25

In vitro

Question 26

What is the transition period for an investigational new drug?

Answer 26

Between animal testing and clinical testing

Question 27

__ is the maximum dose at which a specified toxic effect is not seen

Answer 27

No-effect dose

Question 28

__ is the smallest dose that is observed to kill any experimental animal under a defined set of conditions

Answer 28

Minimum lethal dose (LDmin)

Question 29

__ is the dose that kills approximately 50% of the animals

Answer 29

Medial lethal dose (LD50)

Question 30

__ is measured to assess a drug’s effect (e.g., BP for testing an antihypertensive agent

Answer 30

Endpoint

Question 31

The general strategy for eliminating compounds involves biotransformation into ___ derivatives

Answer 31

More polar, and sometimes larger

-polar and water-soluble products are more readily excreted by the kidneys