Biotransformation, Pharmacogenomics, Clinical Trials

Question 1

Types of drugs that are eliminated through renal excretion:

-characterisitcs

Answer 1

polar compounds or compounds with small molecular volumes

Question 2

What drug route does not undergo first pass effect

Answer 2

parenteral route administrated drugs: non-oral drugs

Question 3

Phase I vs Phase II reactions result in?

Answer 3

phase 1 results in biological inactivation of the drug while phase II reactions produce a metabolite with improved water solubility and increased molecular weight.

Question 4

Phase I reaction types

• more common
• less common

Answer 4

more common is oxidation, reduction, and hydrolysis

less common includes hydroxylation, epoxidation, dealkylation, deamination, desulfuration, dechlorination

Question 5

Enzymes that carry out phase I reactions

(x3)

Answer 5

Cytochrome P450s, Flavin-containing monooxygenases, epoxide hydrolases

Question 6

where are phase I enzymes located?

phase I products vs parent drug?

Answer 6

phase I enzymes are located in the lipophlic ER membranes of the liver

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

Question 7

Phase II rxns

• characteristics of drug conjugates produced
• conjugation dependent on which endogenous substrates?
• rate of conjugation vs phase I rxns?

Answer 7

• drug conjugates are polar molecules w/ higher molecular weight that are readily excreated and often inactive compared to their precursors
• dependent upon endogenous substrates such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid
• conjugation occurs at faster rates than phase I

Question 8

Most important CYPs:

• (x5)
• which is the most common?

Answer 8

CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4

CYP3A4 is the most abundantly expressed

Question 9

how does a CYP work?

-use molecular oxygen (O₂) and H⁺ derived from what?

Answer 9

-use O2 and H derived from the cofactor reduced nicotinamide adenine dinuleotide phosphate (NADPH) to carry out the oxidation of substrates

Question 10

Genetic defect in pseudocholiesterase causes?

Answer 10

that individual to metabolize SUCCx at 50% of normal

Question 11

Slow acetylator phenotype:

• have decrease what levels?
• what types of drugs metabolized slower?
• what populations is this common in?

Answer 11

• AR trait leads to decrease in N-acetyltransferase levels
• isoniazid (TB drug), hydralazine (HTN), caffeine, other amines, metabolized slower and can lead to hepatotoxicity (hepatitis)
• phenotype occurs in about 50% of US population, 83% Frenchies, less common in Asians

Question 12

Enzyme induction:

-examples

Answer 12

phenytoin, chronic ETOH (CYP2E1), aromoatic hydrocarbons like benzo[a]pyrene, rifampin, phenobarbital, other barbituates

Question 13

newborns have trouble metabolizing hemoglobin why?

Answer 13

immature hepatic metabolic pathways–> newborns unable to conjugate bilirubin with UDP glucuronic acid and bilirubin is unable to be excreted

Question 14

Acetaminophen toxicity

Answer 14

Question 15

Define pharmacogenomics

Answer 15

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

Question 16

Define Single Nucleotide Polymorphism

Answer 16

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

Question 17

G6PD deficiency

• MOA of G6PD
• deficiency leads to?

Answer 17

MOA: G6PD produces NADPH which regenerates glutathione from its oxidized form

-reduced glutathione protects cells against oxidative stress/damage, so without it oxidative damage leads to hemolytic anemia in the presence of oxidants

Question 18

OATP1B1

• what does it do?
• what mutation associated w/ reduced membrane expression?
• pts w/ this defect can suffer from _ induced myopathy

Answer 18

• organic Anion Transporter (OATP1B1) responsible for hepatic uptake of weak acidic drugs
• Val74Ala mutation is associated w/ reduced membrane expression–>reduced trafficking
• pts with this mutation suffer from Simvastatin-induced myopathy

Question 19

Enzyme responsible for converting codeine to morphine

Answer 19

CYP2D6

Question 20

Enzyme responsible for activation of Clopidogrel

-polymorphisms cause?

Answer 20

CYP2C19

decreased activity of the drug causing increased risk for adverse CV events. specifically the CYP2C19*2 gene

Question 21

N-acetyltransferase genetic variation:

-causes problems w/ which drug

Answer 21

causes hepatitis w/ isoniazid

Question 22

TPMT, 6-mercaptopurine

-responsible for deactivation of?

Answer 22

responsible for deactivation of thiopurine drugs, 6-mercaptopurine can cause defects in TPMT fxn

Question 23

UGT1A1

• responsible for ?
• mutations lead to?

Answer 23

conjugates glucuronic acid so it can be excreted into bile

UGT1A1-28 mutations lead to increased risk of adverse drug rxns due to reduced biliary elimination

Question 24

Variations associated w/ altered response to warfarin therapy

Answer 24

• VKORC1 results in increased sensitivity to warfarin/ increased bleeding
• CYP2C9 polymorphism results in decreased metabolic clearance of S-Warfarin leading to increased anticoagulation and bleeding

Question 25

What is a lead compound?

Answer 25

chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, and phamacokinetic parameters.

Question 26

no-effect dose

Answer 26

maximum dose at which a specified toxic effect is not seen, just lower than the threshold of harmful effects

Question 27

In vitro cell based study vs in vivo

Answer 27

in vitro--\> lead compounds tested in mammalian cells to see which proteins the drug binds to and/or which pathways it may inhibit or upregulate in vivo--\> drugs tested in mammalian subjects, animals first and then humans

Question 28

goals of preclinical testing: | (x3)

Answer 28

- identify potential human toxicities without human testing - design tests to further define the toxic mechanisms - predict the specific and most relevant toxicities to be monitored in clinical trials

Question 29

Limitations of preclinical testing | (x4)

Answer 29

- time and cost--\> could take 2-6 years - number of animals used--\> cost of mice - extrapolation of values--\> not all toxicities directly translate to humans from animals - rare and adverse events are unlikely to be detected in preclinical animal testing

Question 30

Caveats in human testing | (x3)

Answer 30

- variable natural history and proggression of disease (diseases can increase and decrease in severity over time or spontaneously disappear) - presence of other diseases and risk factors (other drug use can affect results) - subject and observer bias (placebo effect)

Question 31

Double blind

Answer 31

neither the patient nor the physician knows the identity of the therapy the pt is receiving

Question 32

single blind

Answer 32

only the health professional knows the identity of the therapy the pt is receiving

Question 33

open label

Answer 33

both the patient and health professional know the identity of the therapy the pt is receiving

Question 34

parallel trial

Answer 34

a study where one group of pts receives only treatment A and the other group of pts receives only treatment B

Question 35

Crossover trial

Answer 35

pts receive each therapy in sequence so that the pts serve as their own controls

Question 36

Endpoint vs surrogate endpoint

Answer 36

endpoint: the primary outcome measure surrogate endpoint: an endpoint that may correlate with the "real" endpoint but does not necessarily have a guaranteed relationship.

Question 37

Phases of clinical trials phase 0, phase 1

Answer 37

0: subpharmacological doses of prospective drug candidates are administered to human colunteers--\> provides early pharmacokinetic data in humans 1: conducted to determine whether humans and animals show different responses to the investigational drug and establish approximate limits on the safe dosage range

Question 38

phases of clinical trials phase 3

Answer 38

performed on large groups (100-200) that have the target disease to determine its efficacy, dosing requriements, and toxicities

Question 39

phases of clinical trials

Answer 39

only occurs after approval of a drug to go to market post marketing study to continue to monitor safety and efficacy of the drug

Question 40

Investigational new drug: - define - must contain

Answer 40

an application that must be approved before the drug is transported across state lines -must contain preclinical data from animal pharmacology and toxicology studies, manufacturing info, clinical protocols, and investigator info

Question 41

institutional review board: -what does it assure

Answer 41

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

Question 42

new drug application: -define

Answer 42

an application filed with the FDA by a manufacturer of a drug for a license to market the drug for a specific indication.