3. DSA Biotransformation, Pharmacogenomics, and Clinical Trials

Question 1

What is the enzymatically driven process whereby a substance is changed from one chemical to another?

Answer 1

Drug biotransformation

Question 2

The strategy for eliminating compounds is biotransformation into more polar and larger derivatives. The polar and water soluble products are excreted via?

Answer 2

more readily via the kidney

Question 3

Inactivation can be seen due to biotransformation, such as aspiring being made into acetic acid and salicylate. What are the other two consequences that can occur?

Answer 3

Active compound to Active compound

Actication: L dopa to Dopamine = Prodrug

Question 4

What is an inactive drug that undergoes biotransformation to become and active drug? Where does this commonly occur?

Answer 4

prodrug

Occurs in the liver between absorption into the general circulation and renal elimnation

Question 5

Xenobiotics absorbed from the SI are transported to the liver via portal system. What is the process by which oral drugs undergo extensive biotransformation after absorption prior to entering circulation?

Answer 5

First Pass effect (not parenterally administered drugs)

Question 6

First pass effect can be bad, since the drugs are being processed before being able to enter circulation, limiting the bioavailibility of some drugs. What is an alternative route to go around the first pass effect?

Answer 6

Give a drug parenterally

ex: morphine oral bioavailbility is 25%

Question 7

What are the two phases of biotransformation?

Answer 7

1. Reactions which result in inactivation of a drug

2. Reactions produce metabolite with improved water solubility and increased molecular weight to enhance elimination

Question 8

Phase 1 involves enzymes to convert the drug to a more polar metabolite via oxidation, reduction and hydrolysis. Phase 1 products are catabolic and the products can be?

Answer 8

more reactive and more toxic than the parent drug

Question 9

Phase 2 involves enzymes that form a conjugate of the substrate. Conjugation improves water solubility and inc. molecular weight. Phase 2 reactions are?

Answer 9

anabolic (building)

NOTE: isoniazid does not follow Phase 1 to Phase 2

Question 10

All of phase 1 reactions are carried out by mixed function oxidases MFOs or monooxegenases, including what 3?

Answer 10

CYP450
Flavin containing monooxygenases FMO
Epoxide Hydrolases

Question 11

Where does phase one of biotrasnformation occur?

Answer 11

in lipophilic ER membranes of the liver

Question 12

What is the main clinical relevance of biotransformation?

Answer 12

Rate and efficiency differs between individuals, so it may affect drug dose and frequency of administration among individuals

Question 13

There are genetic and nongenetic factors influencing biotransformation (BT), what are two of each?

Answer 13

Genetic: mutation in xenobiotic metabolizing enzymes, pharmacogenetic differences in E expression levels
Nongenetic: age,sex,circadiam rhythm, drug-drug interactions

Question 14

Enzyme induction can occur via rifampin, st john’s wort, enzyme inhibition can occur via grapefruit juice. What are two other non genetic factors that can affect BT?

Answer 14

Age (dec. hepatic blood flow=dec ability to break down)

Disease states such as liver/cardiac disease

Question 15

Acetaminophen-induced hepatotoxicity… when an adult takes too much, the glucuronidation and sulfation pathways are saturated forcing liver to use P450… leading to?

Answer 15

toxic metabolites when GSH is depleted d/t using other pathway

Question 16

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

Answer 16

Pharmacogenetics

Question 17

What is the study of the entire genome to assess multigenetic determinants of drug resopnse?

Answer 17

Pharmacogenomics

Question 18

What is the variation in the rate at which the body absorbs, transports, metabolized, or excretes a drug/metabolite?

Answer 18

Pharmacokinetics

Question 19

What is the allelic variation in a drug’s downstream targets such as receptors, enzymes, or metabolic pathways?

Answer 19

Pharmacodynamics

Question 20

Polymorphisms in CYP450 in phase 1 reactions can result in?

Answer 20

absent, decreased or increased enzyme activity

Question 21

What is the most common disease-producing enzyme defect of humans, which is needed to regenerate glutathione from its oxidized form? (pharmacodynamic response variation)

Answer 21

Glucose-6-phosphate dehydrogenase deficiency (can lead to hemolytic anemia d/t lack of glutathione which protects cells from oxidative damage)

Question 22

Ryanodine receptor mutation and malignant hyperthermia are examples of variations in?

Answer 22

pharmacodynamic response

Question 23

Clinical trials include 4 phases and are often designed to compare?

Answer 23

one form of therapy to another experimental form

Question 24

In vitro studies to animal testing for efficacy selectivity mechanism. To clinical testing:
Phase 1: 20-100subjects, is it safe, pharmacokinetics?
Phase 2: 100-200 subs, does it work in patients?
Phase 3: 1000-6000, does it work double blind
Phase 4?

Answer 24

posmarketing surveillnace (10 years later!)

Question 25

What is the purpose of IRB (institutional review board)?

Answer 25

to assure that appropriate steps are taken to protect the rights, safety, and welfare of humans participating as subjects in the research