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Pharmacology Test #1 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

xenobiotic

A

drug or nonessential exogenous compound

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2
Q

metabolism

A

chemical modification of compounds by enzymes

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3
Q

sites of drug metabolism

A 
liver
gastrointestinal tract
lungs
kidneys
brain
skin
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4
Q

oral bioavailability

A

fraction of total dose that reaches systemic circulation

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5
Q

factors that influence bioavailability

A

solubilty
membrane permeability
P-gp efflux
presystemic first pass metabolism (intestinal, hepatic)

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6
Q

metabolism of a drug where in systemic circulation is most important for most drugs?

A

hepatic metabolism

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7
Q

Phase I drug metabolism

A

chemical modification (biotransformation) including oxidation, hydroxylation, etc. to introduce new functional group or expose group for Phase II reactions

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8
Q

Phase II drug metabolism

A

conjugation of polar group with drug

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9
Q

What is often the purpose of Phase II drug metabolism?

A

usually kills the activity of the drug - used for excretion

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10
Q

termination of xenobiotic action can be caused by which processes?

A

bioinactivation
detoxification
elimination

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11
Q

Bioinactivation and detoxification

A

the drug metabolite may be less active or completely inactive

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12
Q

Elimination

A

metabolism increases the polarity of drug molecules

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13
Q

How do you increase the polarity of drug molecules?

A

decreasing lipid solubility

increasing water solubility

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14
Q

Prodrug

A

the drug metabolite may be more active than the parent compound, or the parent compound may require activation for biological activity (bioactivation)

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15
Q

Toxification

A

compounds may be activated to biologically active metabolites that frequently cause adverse toxic effects

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16
Q

Explain the genotoxicity of polyaromatic hydrocarbons (found in cigarette smoke)

A

Phase I drug metabolism of these compounds can create reactive epoxides on the molecule. The planar molecule can then easily insert into DNA and create mutagenic DNA adducts.

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17
Q

What is the most frequent reason that new therapeutic agents are not approved by the FDA?

A

drug-induced hepatic damage

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18
Q

Explain the hepatoxicity of acetaminophen.

A

Acetaminophen is metabolized by cytochrome P450 to a reactive form that is normally conjugated to glutathione and eliminated. If you take too much acetaminophen you exhaust the supply of glutathione in the liver and the extremely reactive form created by CYP450 starts to react with many other things, causing toxicity.

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19
Q

How many cytochrome P450 enzymes are in humans?

A

57

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20
Q

1/3 of all drugs are metabolized by

A

CYP3A4

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21
Q

1/5 of all drugs are metabolized by

A

CYP2D6

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22
Q

What does the active site of CYP contain?

A

iron-heme confactor

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23
Q

maximal light absorption (Soret peak) of CYPs

A

450 nm

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24
Q

Important intrinsic factors for drug metabolism?

A

topography of protein binding site and steric hindrance of the access to the catalytic heme group

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25
Factors that determine binding strength
coordination strength with heme iron hydrophobic contacts with binding site of CYP specific contacts with binding site residues
26
which molecules typically have a stronger affinity to the heme iron than molecules that coordinate with oxygen or carbon atoms
molecules with nitrogen as sixth iron-coordinating ligand
27
What can stabilizes the ligand-protein binding of CYPs?
additional hydrophobic contacts
28
Azo antifungal drugs (ketoconazole) are?
strong inhibitors for CYPs
29
Mechanism-based inhibition (MBI, suicide inhibition)
metabolism of substrate generates reactive metabolite that irreversibly interacts with the heme or residues in the binding site
30
significance of mechanism-based inhibition
further metabolism of same or other drug is delayed as CYP needs to be resynthesized
31
induction
drugs bind to transcription factor proteins that induce transcription of CYP genes, results in increased metabolism
32
significance of induction
reduced plasma concentrations | increased toxicity if reactive metabolites are formed
33
When do drug-drug interactions occur?
when the efficiency or toxicity of a drug is altered by the co-administration of another drug, food or chemical.
34
mechanism of drug-drug interactions
drug A inhibits (or induces) specific CYP (particularly CYP3A4) that is responsible for metabolization of co-administered drug B (plasma concentration of drug B and A changes)
35
What happens to the bioavailability of lopinavir when it is co-administered with ritonavir?
it increases the bioavailability because lopinavir is a substrate of CYP3A4 and ritonavir is an inhibitor of CYP3A4
36
grapefruit juice contains
bergamottin (MBI or CYP3A4) | naringin (inhibitor of CYP3A4)
37
substrate for CYP1A2
neutral/basic, lipophilic and planar molecules
38
ketoconazole
very strong CYP inhibitor
39
grapefruit juice
can inhibit some types of CYPs
40
rifampin
inducer of some CYPs | causes increased expression of CYPs
41
Name things that CYP2A6 metabolizes
coumarin, nicotine, aflatoxin B1, naproxen, tacrine, clozapine, mexiletine, cyclobenzaprine; bioactivates nitrosamines and procarcinogens
42
Name things that CYP2B6 metabolizes
cyclophosphamide, ifosfamide, bupropion and nicotine
43
Name things that CYP2C8/9 metabolizes
tricyclic antidepressants (e.g. diazepam, verapamil)
44
Where is CYP2C8/9 expressed
mainly in extrahepatic tissues
45
Name things that CYP2C19 metabolizes
basic compounds, frequently containing C=O or S=O groups; antiepileptics, proton-pump inhibitors
46
Which is the most important isoenzyme of the CYP2C subfamily?
CYP2C9
47
Describe the substrates for CYP2C9
neutral/acidic, amphipathic with a hydrophobic region near oxidation
48
What is the general structure of things metabolized by CYP2D6?
lipophilic amines; prefers ion-pair interactions
49
Name some classes of drugs metabolized by CYP2D6
cardiovascular drugs, beta-adrenergic receptor blockers, tricyclic antidepressants, antipsychotics, SSRIs, H1-blockers, opioids
50
What inhibits CYP2D6?
quinidine, fluoxetine, bupropion
51
Describe the specificity of CYP3A4
low substrate specificity | compounds that bind to CYP3A4 are structurally diverse
52
Name some things that are metabolized by CYP3A4
macrolide antibiotics, antiarrhythmics, benzodiazepines, immune modulators, HIV antivirals, antihistamines, calcium channel blockers, HMG CoA reductase inhibitors, and many others
53
CYP3A4 is inhibited by?
HIV antivirals, clarithromycin, itraconazole, ketoconazole, saquinavir etc
54
CYP3A4 is induced by?
barbituates and HIV antivirals
55
Name some other phase I enzymes besides the CYPs
``` Flavin-containing monooxygenase Alcohol dehydrogenase Monoamine oxidase Esterase Amidase Epoxide hydrolase ```
56
What do Phase II reactions do?
couple drug or activated drug (by phase I reactions) with conjugates (typically polar groups) bioinactivate and detoxification typically
57
Most dominant phase II enzymes
UGTs | uridine 5'-diphosphate [UDP]-glucuronosyl transferases
58
Many functional groups can form glucuronide conjugates, why don't you name some important ones?
O-glucuronidation N-glucuronidation S-glucuronidation
59
What does UGTs do?
conjugates glucuronic acid component of UDPGA to a drug
60
What's important about where UGT and P450 are located?
they're spatially co-localized on the ER so a phase-I metabolite can be further metabolized by UGT without a long path between both reactions
61
What do glutathione S-transferases (GST) do?
glutathione conjugation for nitrosaureas, mustard-type anticancer drugs
62
What do sulfotransferases metabolize?
steroid hormones, catecholamine neurotransmitters, phenolic drugs
63
Which phase II enzyme does O-, N-, S-methylation?
methyltransferases
64
General categories of possible external factors in drug metabolism?
genetic factors physiologic factors pharmacodynamic factors environmental factors
65
What happened when chloramphenicol was IV administered to newborns for treatment of meningitis?
gray baby syndrome | UGT system immature and the drug concentration reached toxic levels
66
What is significant about CYP3A4/7 expression and age?
CYP3A4/7 expression is different pre-natal and post-natal | they have overlapping but different drug specificity and regioselectivity/reactivity profiles
67
What happens to some CYPs expression profiles in the first weeks after birth?
displays hypervariability
68
what pumps xenobiotics out of fetal circulation?
P-gp (P-glycoprotein)
69
Describe the passage of drugs from mother to infant
Most xenobiotics in maternal circulation cross the placenta fairly efficiently
70
What is not fully functional in a baby
UGT system
71
Name some problems with drug metabolism and old people
often taking many drugs (interactions) decreased hepatic blood flow (reduced 1st-pass metabolism) decreased hepatic mass (reduction of phase I metabolic reactions) decreased renal blood flow (decreased renal excretion)
72
What diseases can significantly affect hepatic drug metabolism
acute and chronic liver diseases | cardiac diseases can decrease blood flow to liver
73
Three types of drug metabolizers people can be
``` poor metabolizer (PM) extensive metabolizer (EM) ultrarapid metabolizer (URM) ```
74
describe consequences for poor metabolizers
greater potential for drug-drug interactions and adverse effects slower bioactivation of prodrug (lower efficacy)
75
describe consequences for ultrarapid metabolizers
greater rate of drug elimination (lower efficacy) | greater potential for generating toxic metabolites

Pharmacology Test #1 (5 decks)

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