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01. Skin, Blood, and Lymph Exam 1 > Lecture 6: Intro to Biotransformation, Pharmacogenomics, and Clinical Drug Trials > Flashcards

Lecture 6: Intro to Biotransformation, Pharmacogenomics, and Clinical Drug Trials Flashcards

1
Q

What is the general strategy for eliminating compounds from the body?

A

Biotransformation of xenobiotics into more polar (and sometimes larger) and water soluble derivatives

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2
Q

Biotransformation may convert an inactive drug (pro-drug) to an active one, may lead to a product that is still active, or may inactivate a compound.

Provide an example of each.

A
  • Activation:
    1) L-dopa (pro-drug) –> dopamine
  • Active compound –> Active compound:
    2) Diazepam –> Oxazepam
  • Inactivation:
    3) Acetylsalicylic acid (aspirin) –> acetic acid + salicylate
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3
Q

T/F drugs that are given via parenteral routes of administration undergo first-pass biotransformation?

A

False

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4
Q

What is the classic example of a drug that undergoes extensive first-pass biotransformation?

A
  • Morphine
  • Bioavailability of oral preparations is roughly 25%; parenteral administration is preferred
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5
Q

What happens in the phase I reactions vs. phase II reactions?

Which phase is anabolic vs. catabolic?

Where does each phase occur and which is fastest?

A

Phase I: makes it inactive (oxidation, reduction, hydrolysis); catabolic; products are generally more reactive and toxic; enzymes located in the lipophilic ER membranes of liver

Phase II: conjugation making the substrate more water soluble and increases MW (anabolic); occurs faster than phase I rxns; takes place in liver

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6
Q

Phase I reactions are carried out by what 3 types of enzymes?

A

Mixed function oxidases (MFOs) or monooxygenases

1) CYP450s *primary phase I enzymes
2) Flavin-containing monooxygenases (FMO)
3) Epoxide hydrolases (mEH, sEH)

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7
Q

What is unique about the metabolism of isoniazid?

A

Phase II reaction occurs first (conjugation)

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8
Q

What are examples of phase II enzymes?

A
  • UGT, GST, NAT (n-acetyltransferase)
  • TPMT (thiopurine methyltransferase)
  • SULT (sulfotransferase)
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9
Q

Which CYP is the most abundantly expressed and involved in the metabolism of about 50% of clinically used drugs?

A

CYP3A4

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10
Q

People with genetic defects in which enzyme can metabolize succinylcholine at 50% the rate of normal individuals?

A

Pseudocholinesterase

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11
Q

What is the slow acetylator phenotype?

Causes the slow metabolism of which compounds?

A
  • AR trait w/ decrease in N-acetyltransferase levels in the liver
  • Isoniazid, hydralazine, caffeine and other amines
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12
Q

Consumption of grapefruit juice with drugs taken orally can irreversibly inhibit what?

A

Intestinal CYP3A4

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13
Q

Which drug given with Mercaptopurine prolongs the duration of Mercaptopurines action and enhances its chemotherapeutic and toxic effects?

Why?

A
  • Allopurinol by inhibiting xanthine oxidase
  • Xanthine oxidase is a key enzyme in the biotransformation pathway of mercaptopurine
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14
Q

What is the most important factor accounting for decreased drug metabolism in elderly patients?

A

Liver and kidney disease

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15
Q

How does acetaminophen intake exceeding therapeutic dose lead to biotransformation into more toxic products and acetaminophen-induced hepatotoxicity?

A
  • Hepatic GSH is depleted faster than regenerated
  • Toxic metabolites accumulate resulting in hepatotoxicity
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16
Q

Levels of which drugs with flow-limited biotransformation may rise if given to patients with cardiac disease?

A
  • Atenolol and propranolol (beta blockers)
  • Isoniazid
  • Lidocaine
  • Morphine
  • Verapamil
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17
Q

In vitro studies with a lead compound are used to study what?

Which type of cellular system is used?

A
  • Factors involved in the drug’s actions (i.e., proteins the drug may bind to and/or the pathways it may inhibit or regulate)
  • Helps establish the direct drug target or effects (pharmacologic profile) at the molecular and cellular levels
  • Ideally tested in a cellular system that best represents the disease state the therapy is targeting
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18
Q

What is the No-effect dose?

A
  • Maximum dose at which a specified toxic effect is not seen
  • Lower than the threshold of harmful effect and is oftn estimated while establishing the threshold of harmful effect
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19
Q

Minimum lethal dose (LDmin) vs. Median lethal dose (LD50)?

A
  • LDmin: the smallest dose that is observed to kill any experimental animal under a defined set of conditions
  • LD50: the dose that kills approximately 50% of the animals
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20
Q

What are 3 limitations to preclinical testing?

A

1) Time and cost: 2-6 yrs may be required to collect and analyze animal toxicity profiles and estimate the therapeutic index
2) Number of animals used: cost associated w/ maintenance of a single mouse can be upwards of $400/year/cage
3) Extrapolation of values: toxicity and therapeutic values in animals often translate to humans, but many do not

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21
Q

What is a crossover design in human clinical trials?

A
  • Patients receive each therapy in sequence so that the patients serve as their own controls
  • They will receive both the drug and placebo at different times during the study
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22
Q

What is a single-blind vs. double-blind design in clinical trials?

A
  • Single-blind: only the health professionals known the identity of the tx
  • Double-blind: neither the pt nor the health professional knows the identity of the therapy
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23
Q

What is an Investigational new drug (IND)?

A
  • Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines
  • Submission of the IND is the means by which investigators technically obtain permission from the FDA to proceed w/ drug distribution
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24
Q

What is Phase 0 of a clinical trial and its advantages?

A
  • Also termed microdosing; provide early pharmacokinetic data in humans and only require minimal preclinical toxicology safety testing
  • Useful in situations where in vitro and animal models prove to be unreliable
  • Also financially advantageous
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25
Q

What is Phase I of clinical trials, how many subjects involved, and what information is obtained?

A
  • Determines whether humans and animals show significantly different response to the drug and establishing probably limits of the safe cllinial dosage range
  • 25-50 volunteers
  • Absorption, half-life, and metabolism are typical data reported
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26
Q

What is Phase II of clinical trials, how many subjects involved, and what information is obtained?

A
  • Typically single-blind, involving 100-200 patients
  • Include an inert placebo, established active drug (positive control), and active investigational agent
  • Efficacy, dosing, and toxicities are detected and recorded

*Drug failure typically occurs during this phase when drug is discovered to be toxic or not efficacious at appropriate doses

27
Q

During which phase of clinical trials does drug failure typically occur?

A

Phase II

28
Q

What is Phase III of clinical trials, how many subjects involved, and what information is obtained?

A
  • Further established drug safety and efficacy, using large group of patients (300-3000+)
  • Crossover and double-blind methods are often used to minimize errors and other bias
  • Intent is to gather additional info to evaluate overall benefit-risk relationship of drug and provide adequate basis for physician labeling
  • The most expensive phase due to large number of patients and data
29
Q

What is Phase IV of clinical trials?

A
  • Only after approval to market a new drug does this phase begin
  • Purpose is to continue to monitor the safety of the new drug
  • Allows for the identification of rare drug-induced effects or toxicities
30
Q

How are individuals defined in terms of their metabolizing ability based on their allelic activity scores?

A

0 = Poor Metabolizer

0.5 = Intermediate Metabolizer

1-2 = Extensive Metabolizer

>2 = Ultra-rapid metabolizer

31
Q

Which CYP2D6 alleles are nonfunctional, reduced function, and fully functional?

A

*1 and 2 are fully functional

*3-6 are nonfunctional

*10, 17, and 41 have reduced function

32
Q

What is the most common nonfunctional CYP2D6 allele?

A

CYP2D6*4

33
Q

What is the active metabolite of Codeine and which enzyme is responsible for this conversion?

A
  • Morphine
  • CYP2D6
34
Q

What does CYP2C19 metabolize?

A

Acidic drugs (PPIs, antidepressants, antiepileptics, and antiplatelet drugs)

35
Q

Which CYP2C19 alleles are fully functional, nonfunctional, and which have increased function?

A

*1 is fully functional

*2-3 are non-functional

*17 has increased function

36
Q

How does the presence of an CYP2C19*17 allele affect a patient with another nonfunctional CYP2C19 allele?

What type of phenotype will this patient have?

A
  • Although *17 has increased function, it is unable to fully compensate for nonfunctional alleles
  • Would still be considered an IM phenotype
37
Q

What is the most common nonfunctional allele of CYP2C19 and who is it seen most prevalent in?

A
  • CYP2C19*2
  • Asians
38
Q

Carriers of the nonfunctional CYP2C19*2 are at an increased risk of cardiovascular events, particularly acute coronary syndrome, when taking which drug?

A

Clopidogrel

39
Q

What is Dihydropyrimidine dehydrogenase (DPD)?

A

First and rate-limiting step in pyrimidine catabolism, as well as major elimination route for fluoropyrimidine chemotherapy agents

40
Q

What is the most commonly observed nonfunctional allele of DPYD?

A

DPYD*2A

41
Q

The presence of nonfunctional DPYD gene must be considered when administering which drug?

How is this drug typically given?

A
  • Fluoropyrimidine drugs (5-FU (active compound), capecitabine, and tegafur)
  • Converted to active, cytotoxic metabolites 5-FUMP and 5-FdUMP, which target cancer cells, but can build up if patients has a nonfunctional DPYD
  • 5-FU must be administered IV
42
Q

What is the most common nonfunctional allele of UGT1A1?

A

UGT1A1*28

43
Q

Patients with nonfunctional UGT1A1 (*28 and *6) are at increased risk for severe life-threatening toxicities when taking which drug?

Due to decreased clearance of which metabolite?

A
  • Irinotecan (topoisomerase I inhibitor)
  • SN-38 metabolite
44
Q

What is the significance of Glucose 6-phosphate dehydrogenase (G6PD)?

A
  • First and rate-limiting step in the pentose phosphate pathway and supplies a significant amound of reduced NADPH in the body
  • In RBCs, is the exclusive source of NADPH and reduced glutathione, necessary for prevention of oxidative damage
45
Q

What are the 5 classifications for G6PD deficiency, normal, and enhanced activity?

Amount of enzyme activity?

Associated pathologies?

A

I: severe deficiency; <10%; chronic (non-spherocytic) hemolytic anemia

II: severe deficiency; <10%; acute hemolytic anemia; intermittent hemolysis

III: moderate deficiency; 10-60%; acute hemolytic anemia; hemolysis w/ stressors

IV: no deficiency; 60-150%; normal

V: no deficiency; >150%; enhanced activity

46
Q

The majority of G6PD-deficient genotypes are associated with which categoery set forth by the WHO?

A

Class II (severe) and class III (moderate)

47
Q

Patients with G6PD deficiency receiving which drug are at greatly increased risk for severe hemolytic anemia and methemoglobinemia?

A

Rasburicase; used in management of high uric acid levels in cancer patients undergoing chemo; produces high levels of hydrogen peroxide

48
Q

Patients with reduced OATP1B1 function may experience adverse side effects when taking which drug?

A

Simvastatin

49
Q

What are the well known enzyme (CYP) inducers?

A
  • Phenobarbital
  • Chronic ethanol
  • Armoatic hydrocarbons (tobacco smoke)
  • Rifampin
  • St. Johns wort
50
Q

The OATP1B1 transporter (encoded by the SLCO1B1 gene) located on th sinusoidal membrane of hepatocytes is resonsible for the hepatic uptake of?

A

Mainly weakly acidic drugs and endogenous compounds i.e., statins, methotrexate, and bilirubin

51
Q

A reduced function variant in ABCG2, which encodes BCRP has been associated with pharmacokinetic changes in response to which drugs?

A
  • Allopurinol
  • Rosuvastatin
  • Toxicity to various anticancer drugs
52
Q

Which HLA polymorphism is associated with hypersensitivity reactions, particularly SJS, in patients receiving HIV treatment with Abacavir?

A

HLA-B* 57:01

53
Q

Genetic variants found near which gene were found to be the most significantly associated w/ HCV tx response to PEG-IFN-α in combo w/ ribavirin?

A

IFNL3 gene encoding IFN-λ3 (aka IL-28B)

54
Q

What is the drug target for Warfarin (pharmacodynamics)?

A

Vitaming K epoxide reductase complex subunit 1 (VKORC1)

55
Q

Pharmacokinetic polymorphisms in which enzyme may lead to an increased risk of bleeding in patients on Warfarin therapy?

A

CYP2C9 (specifically CYP2C9*3 and *2)

56
Q

Pharmacodynamic polymorphisms in which gene may lead to bleeding disorders or increased drug sensitivity in a patient on Warfarin?

A

VKORC1

57
Q

What is a surrogate endpoint?

A

An outcome of therapy that predicts the real goal of therapy without being that goal (i.e., reduction in tumor size as a surrogate for survival)

58
Q

Define the term Open Label in regards to research?

A

Both health professionals and patients know whether the drug is the experimental or control agent

59
Q

Define Parallel trial

A

At least 2 regimens are tested simultaneously, but patients are assigned to only one therapy

60
Q

What is an Endpoint in a clinical trial?

A

Measured to assess a drug’s effect (i.e., blood pressure is the endpoint for testing an antihypertensive agent)

61
Q

What receptor mutation may cause malignant hyperthermia; what is the MOA?

A
  • Ryanodine receptor mutation
  • Inhalation of succinylcholine activates receptor –> increased Ca2+ in sarcoplasm of muscle leads to muscle rigidity, elevated body temp, and rhabdomyolysis
62
Q

What is the acute toxicity test; how many species and routes?

Determines what?

A
  • Usually 2 species, 2 routes
  • Determines the no-effect dose and the maximum tolerated dose
63
Q

When is the carcinogenic potential test required; how long and how many species used?

Determines what?

A
  • Two years, two species
  • Required when drug is intended to be used in humans for prolonged periods
  • Determines gross and histologic pathology

01. Skin, Blood, and Lymph Exam 1 (6 decks)

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