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Biotransformation, clinical trials, etc. Flashcards

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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
Examples of drug levels that may rise due to cardiac disease and lower rates of elimination
beta blockers, isoniazid, lidocaine, morphine, verapamil
26
Examples of important detoxifying substrates
glutathione, glucuronic acid, sulfate
27
Pharmacogenetics
study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, toxicity at genomic level
28
Pharmacogenomics
study of entire genome to assess multigenetic determinants of drug response
29
Allele
one of two or more alternative forms of a gene
30
polymorphism
variation in DNA sequence
31
Single nucleotide polymorphism
base pair substitutions that occur in the genome
32
CYP2D6
involved in phase I biotransformation, highly polymorphic
33
Enzyme responsible for O-demethylation conversion of codeine into morphine
CYP2D6
34
Individuals with polymorphisms in CYP2D6 may experience what kinds of side effects when taking codeine
drowsiness, respiratory depression, insufficient pain relief
35
CYP2C19 metabolizes what drugs?
acidic; proton pump inhibitors, antidepressants, antiepileptics, antiplatelet
36
Clopidogrel clinical use
antiplatelet prodrug indicated to prevent atherothrombotic events
37
How is clopidogrel metabolized?
85% by hepatic esterases, 15% by CYP2C19
38
Carriers of CYP2C19 polymorphisms that take clopidogrel are at increased risk for...
adverse cardiovascular events
39
Uridine 5'-Diphosphoglucuronosyl Transferase 1 (UGT1A1)
conjugates glucuronic acid into small lipophilic molecules that can be excreted into bile
40
Irinotecan clinical use
topoisomerase I inhibitor, first-line chemotherapy
41
Irinotecan biotransformation
hydrolyzed by hepatic carboxylesterase enzymes to cytotoxic metabolite; SN-38 is the active metabolite
42
SN-38 is inactivated by what enzyme?
UGT1A1
43
Thiopurine S-Methyltransferase (TPMT)
attaches a methyl group onto aromatic and heterocyclic sulfhydryl compounds
44
Clinical uses of Azathioprine and 6-MP
treating immunologic disorders
45
Clinical uses of 6-MP and 6-TG
anticancer agents
46
Enzyme responsible for activation of 6-MP and 6-TG
HGPRTase
47
Enzymes responsible for inactivation of 6-MP and 6-TG
xanthine oxidase and TPMT
48
Glucose 6-phosphate dehydrogenase
first and rate-limiting step in pentose phosphate pathway, supplies NADPH in the body
49
Source of NADPH and reduced glutathione in RBCs
G6PD
50
What may cause an increase in G6PD activity in RBC?
decreased NADPH caused by infection, fava beans, and therapeutic drugs
51
G6PD deficiency is associated with increased risk for what
RBC destruction and hemolysis
52
Rasburicase clinical use
management of high uric acid levels in CA patients receiving chemotherapy
53
How does rasburicase alleviate the uric acid burden caused by tumor-lysing treatments?
converting uric acid to allantoin
54
Individuals taking rasburicase with a G6PD deficiency are at increased risk for what?
severe hemolytic anemia and methemoglobinemia
55
OATP1B1 transporter
responsible for hepatic uptake of mainly weak acid drugs and endogenous compounds such as statins, methotrexate, and bilirubin
56
HMG-CoA reductase inhibitors
statin, widely used to reduce serum lipids to prevent CV events
57
OATP1B1 genetic alteration that may cause simvastatin toxicity
rs4149056 in SLCO1B1
58
Two genes that effect warfarin
CYP2C9 and VKORC1
59
Drugs that CYP2C9 acts on
acidic drugs - warfarin, phenytoin, NSAIDs
60
CYP2C9 alleles commonly seen in European populations
CYP2C9*2 and *3
61
CYP2C9 alleles commonly seen in African populations
CYP2C9*5, *6, *8, and *11
62
Vitamin K epoxide reductase complex subunit 1
key enzyme in vitamin K recycling and important target for warfarin
63
Vitamin K is essential for activation of what cofactors?
II, VII, IX, and X; protein C and protein S
64
Important consequences of VKORC1 polymorphism
increased sensitivity to warfarin
65
When was the Food, Drug, and Cosmetic Act passed?
1938
66
Six approaches to drug discovery and development
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
Lead Compound
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
Goals of in vitro and in vivo drug tests
ID potential human toxicities, design tests to define toxic mechanisms, predict specific and most relevant toxicities to be monitored
69
No-effect dose
maximum dose at which a specified toxic effect is not seen
70
Minimum lethal dose
smallest dose observed to kill any experimental animal under a defined set of conditions
71
Median lethal dose
dose that kills approx. 50% of animals
72
Purpose of clinical trials
test safety and efficacy of new drugs in humans
73
Crossover design
patients receiving each therapy in sequence so that patients serve as their own controls
74
Placebo effect
inert medicine or ineffective therapy alters a patient's symptoms in some way
75
Single-blind design
only health professionals know ID of treatment
76
Double-blind design
patient nor health professional know therapy ID
77
Purpose of IRB
to assure appropriate steps are taken to protect rights, safety and welfare of humans participating in research
78
Phase 0 clinical trial
subpharmacological doses of drug are administered to volunteers
79
What kind of data may a phase 0 clinical trial provide?
early pharmacokinetic data on humans
80
Phase I clinical trial
first stage of drug testing in humans
81
Purpose of phase I clinical trial
observe whether or not there are significant differences between human and animal responses
82
Number of participants in phase I clinical trials
25-50
83
Phase II clinical trial
single-blind design with 100-200 patients
84
Data detected and recorded in phase II trials
efficacy, dosing requirements, toxicities
85
Phase II clinical trial goals
establish drug safety and efficacy in a larger group of patients (300-3,000)
86
New Drug Application
application submitted by manufacturer of a drug to FDA for license to market drug
87
Phase IV clinical trials
post marketing study to continue to monitor the safety of the drug

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