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SBL > Biotransformation, clinical trials, etc. > Flashcards

Biotransformation, clinical trials, etc. Flashcards

1
Q

biotransformation

A

enzymatically-driven process whereby a substance is changed from one chemical to another by a chemical reaction; chemical modification of lipophilic, unionized, large compounds to terminate their actions and facilitate elimination

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2
Q

Prodrug

A

inactive drug that undergoes biotransformation to become an active drug

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3
Q

Sites of biotransformation

A

liver, kidneys, GI tract, lungs, skin, kidneys; enzymes in ER, mitochondria, cytosol, lysosomes, plasma membrane

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4
Q

First-pass effect

A

process by which drugs are absorbed in the small intestine and transported to the liver via the hepatic portal system, undergo extensive metabolism

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5
Q

Phase I reactions result in…

A

biological inactivation

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6
Q

Phase II reactions result in…

A

improved water solubility and increased molecular weight

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7
Q

What functional groups may be added to a drug to increase it’s polarity?

A

-OH, -NH2, -SH, -COOH, -O

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8
Q

Most common phase I reactions

A

oxidation, reduction, hydrolysis

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9
Q

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

A

CYP450s, Flavin-containing monooxygenases, epoxide hydrolases

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10
Q

Conjugation of drugs is dependent on which endogenous substrates

A

glucuronic acid, sulfuric acid, acetic acid, amino acid

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11
Q

Five most important CYP450s

A

CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4

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12
Q

How do P450s carry out their oxidation of substrates?

A

use O2 and H derived from NADPH

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13
Q

Biotransformation is dependent on what factors?

A

drug-drug interactions, age, sex, circadian rhythm, body temp, liver size and function, environment, genetics

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14
Q

A genetic defect in pseudocholinesterase causes what?

A

succinylcholine metabolism at 50% the rate of normal individuals

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15
Q

Slow acetylator phenotype results in…

A

decrease in N-acetyltransferase levels in the liver

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16
Q

What drugs may be metabolized more slowly as a result of the slow acetylator phenotype?

A

isoniazid, hydralazine, caffeine

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17
Q

Well-characterized enzyme inducers

A

phenytoin, chronic ethanol, benzo[a]pyrene, rifampin, phenobarbital and other barbituates

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18
Q

Grape juice effect on enzyme inhibition

A

Irreversibly inhibits intestinal CYP3A4, inhibits bioavailability of antihypertensives, immunosuppressant, antidepressants, antihistamines, and statins

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19
Q

Clinical use of allopurinol

A

gout, inhibits xanthine oxidase

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20
Q

Clinical use of mercaptopurine

A

immunosuppressive agent used for CA treatment; xanthine oxidase is an important enzyme for biotransformation

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21
Q

Interaction that can occur between mercaptopurine and allopurinol

A

coadministration prolongs the duration of mercaptopurine action and enhances it’s toxic effects

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22
Q

Speed of drug biotransformation throughout life time

A

slow in neonate, increases rapidly in postnatal period, heterogenous in elderly

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23
Q

What developmental issues may male the fetus or neonate more susceptible to drug toxicity?

A

Poorly developed blood brain barrier, weak biotransforming activity, immature excretion mechanisms

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24
Q

What are the most important factors to consider for decreased drug metabolism in the elderly?

A

Liver and kidney disease

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25
Q

Examples of drug levels that may rise due to cardiac disease and lower rates of elimination

A

beta blockers, isoniazid, lidocaine, morphine, verapamil

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26
Q

Examples of important detoxifying substrates

A

glutathione, glucuronic acid, sulfate

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27
Q

Pharmacogenetics

A

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

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28
Q

Pharmacogenomics

A

study of entire genome to assess multigenetic determinants of drug response

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29
Q

Allele

A

one of two or more alternative forms of a gene

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30
Q

polymorphism

A

variation in DNA sequence

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31
Q

Single nucleotide polymorphism

A

base pair substitutions that occur in the genome

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32
Q

CYP2D6

A

involved in phase I biotransformation, highly polymorphic

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33
Q

Enzyme responsible for O-demethylation conversion of codeine into morphine

A

CYP2D6

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34
Q

Individuals with polymorphisms in CYP2D6 may experience what kinds of side effects when taking codeine

A

drowsiness, respiratory depression, insufficient pain relief

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35
Q

CYP2C19 metabolizes what drugs?

A

acidic; proton pump inhibitors, antidepressants, antiepileptics, antiplatelet

36
Q

Clopidogrel clinical use

A

antiplatelet prodrug indicated to prevent atherothrombotic events

37
Q

How is clopidogrel metabolized?

A

85% by hepatic esterases, 15% by CYP2C19

38
Q

Carriers of CYP2C19 polymorphisms that take clopidogrel are at increased risk for…

A

adverse cardiovascular events

39
Q

Uridine 5’-Diphosphoglucuronosyl Transferase 1 (UGT1A1)

A

conjugates glucuronic acid into small lipophilic molecules that can be excreted into bile

40
Q

Irinotecan clinical use

A

topoisomerase I inhibitor, first-line chemotherapy

41
Q

Irinotecan biotransformation

A

hydrolyzed by hepatic carboxylesterase enzymes to cytotoxic metabolite; SN-38 is the active metabolite

42
Q

SN-38 is inactivated by what enzyme?

A

UGT1A1

43
Q

Thiopurine S-Methyltransferase (TPMT)

A

attaches a methyl group onto aromatic and heterocyclic sulfhydryl compounds

44
Q

Clinical uses of Azathioprine and 6-MP

A

treating immunologic disorders

45
Q

Clinical uses of 6-MP and 6-TG

A

anticancer agents

46
Q

Enzyme responsible for activation of 6-MP and 6-TG

A

HGPRTase

47
Q

Enzymes responsible for inactivation of 6-MP and 6-TG

A

xanthine oxidase and TPMT

48
Q

Glucose 6-phosphate dehydrogenase

A

first and rate-limiting step in pentose phosphate pathway, supplies NADPH in the body

49
Q

Source of NADPH and reduced glutathione in RBCs

A

G6PD

50
Q

What may cause an increase in G6PD activity in RBC?

A

decreased NADPH caused by infection, fava beans, and therapeutic drugs

51
Q

G6PD deficiency is associated with increased risk for what

A

RBC destruction and hemolysis

52
Q

Rasburicase clinical use

A

management of high uric acid levels in CA patients receiving chemotherapy

53
Q

How does rasburicase alleviate the uric acid burden caused by tumor-lysing treatments?

A

converting uric acid to allantoin

54
Q

Individuals taking rasburicase with a G6PD deficiency are at increased risk for what?

A

severe hemolytic anemia and methemoglobinemia

55
Q

OATP1B1 transporter

A

responsible for hepatic uptake of mainly weak acid drugs and endogenous compounds such as statins, methotrexate, and bilirubin

56
Q

HMG-CoA reductase inhibitors

A

statin, widely used to reduce serum lipids to prevent CV events

57
Q

OATP1B1 genetic alteration that may cause simvastatin toxicity

A

rs4149056 in SLCO1B1

58
Q

Two genes that effect warfarin

A

CYP2C9 and VKORC1

59
Q

Drugs that CYP2C9 acts on

A

acidic drugs - warfarin, phenytoin, NSAIDs

60
Q

CYP2C9 alleles commonly seen in European populations

A

CYP2C9*2 and *3

61
Q

CYP2C9 alleles commonly seen in African populations

A

CYP2C9*5, *6, *8, and *11

62
Q

Vitamin K epoxide reductase complex subunit 1

A

key enzyme in vitamin K recycling and important target for warfarin

63
Q

Vitamin K is essential for activation of what cofactors?

A

II, VII, IX, and X; protein C and protein S

64
Q

Important consequences of VKORC1 polymorphism

A

increased sensitivity to warfarin

65
Q

When was the Food, Drug, and Cosmetic Act passed?

A

1938

66
Q

Six approaches to drug discovery and development

A
  1. ID or elucidation of new target
  2. Rational drug design of new drug based on understanding of mechanisms and structures
  3. Chemical modification of a known molecule
  4. Screening for biologic activity of large numbers of natural products
  5. Biotech and using genes to produce proteins and peptides
  6. Combos of drugs known to obtain additive or synergistic effects
67
Q

Lead Compound

A

chemical compound that has pharmacological or biological activity, whose chemical structure is used as a starting point to improve potency, selectivity, or pharmacokinetic parameters

68
Q

Goals of in vitro and in vivo drug tests

A

ID potential human toxicities, design tests to define toxic mechanisms, predict specific and most relevant toxicities to be monitored

69
Q

No-effect dose

A

maximum dose at which a specified toxic effect is not seen

70
Q

Minimum lethal dose

A

smallest dose observed to kill any experimental animal under a defined set of conditions

71
Q

Median lethal dose

A

dose that kills approx. 50% of animals

72
Q

Purpose of clinical trials

A

test safety and efficacy of new drugs in humans

73
Q

Crossover design

A

patients receiving each therapy in sequence so that patients serve as their own controls

74
Q

Placebo effect

A

inert medicine or ineffective therapy alters a patient’s symptoms in some way

75
Q

Single-blind design

A

only health professionals know ID of treatment

76
Q

Double-blind design

A

patient nor health professional know therapy ID

77
Q

Purpose of IRB

A

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

78
Q

Phase 0 clinical trial

A

subpharmacological doses of drug are administered to volunteers

79
Q

What kind of data may a phase 0 clinical trial provide?

A

early pharmacokinetic data on humans

80
Q

Phase I clinical trial

A

first stage of drug testing in humans

81
Q

Purpose of phase I clinical trial

A

observe whether or not there are significant differences between human and animal responses

82
Q

Number of participants in phase I clinical trials

A

25-50

83
Q

Phase II clinical trial

A

single-blind design with 100-200 patients

84
Q

Data detected and recorded in phase II trials

A

efficacy, dosing requirements, toxicities

85
Q

Phase II clinical trial goals

A

establish drug safety and efficacy in a larger group of patients (300-3,000)

86
Q

New Drug Application

A

application submitted by manufacturer of a drug to FDA for license to market drug

87
Q

Phase IV clinical trials

A

post marketing study to continue to monitor the safety of the drug

SBL (21 decks)

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