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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
Q

Factors that determine binding strength

A

coordination strength with heme iron
hydrophobic contacts with binding site of CYP
specific contacts with binding site residues

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26
Q

which molecules typically have a stronger affinity to the heme iron than molecules that coordinate with oxygen or carbon atoms

A

molecules with nitrogen as sixth iron-coordinating ligand

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27
Q

What can stabilizes the ligand-protein binding of CYPs?

A

additional hydrophobic contacts

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28
Q

Azo antifungal drugs (ketoconazole) are?

A

strong inhibitors for CYPs

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29
Q

Mechanism-based inhibition (MBI, suicide inhibition)

A

metabolism of substrate generates reactive metabolite that irreversibly interacts with the heme or residues in the binding site

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30
Q

significance of mechanism-based inhibition

A

further metabolism of same or other drug is delayed as CYP needs to be resynthesized

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31
Q

induction

A

drugs bind to transcription factor proteins that induce transcription of CYP genes, results in increased metabolism

32
Q

significance of induction

A

reduced plasma concentrations

increased toxicity if reactive metabolites are formed

33
Q

When do drug-drug interactions occur?

A

when the efficiency or toxicity of a drug is altered by the co-administration of another drug, food or chemical.

34
Q

mechanism of drug-drug interactions

A

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
Q

What happens to the bioavailability of lopinavir when it is co-administered with ritonavir?

A

it increases the bioavailability because lopinavir is a substrate of CYP3A4 and ritonavir is an inhibitor of CYP3A4

36
Q

grapefruit juice contains

A

bergamottin (MBI or CYP3A4)

naringin (inhibitor of CYP3A4)

37
Q

substrate for CYP1A2

A

neutral/basic, lipophilic and planar molecules

38
Q

ketoconazole

A

very strong CYP inhibitor

39
Q

grapefruit juice

A

can inhibit some types of CYPs

40
Q

rifampin

A

inducer of some CYPs

causes increased expression of CYPs

41
Q

Name things that CYP2A6 metabolizes

A

coumarin, nicotine, aflatoxin B1, naproxen, tacrine, clozapine, mexiletine, cyclobenzaprine;
bioactivates nitrosamines and procarcinogens

42
Q

Name things that CYP2B6 metabolizes

A

cyclophosphamide, ifosfamide, bupropion and nicotine

43
Q

Name things that CYP2C8/9 metabolizes

A

tricyclic antidepressants (e.g. diazepam, verapamil)

44
Q

Where is CYP2C8/9 expressed

A

mainly in extrahepatic tissues

45
Q

Name things that CYP2C19 metabolizes

A

basic compounds, frequently containing C=O or S=O groups; antiepileptics, proton-pump inhibitors

46
Q

Which is the most important isoenzyme of the CYP2C subfamily?

A

CYP2C9

47
Q

Describe the substrates for CYP2C9

A

neutral/acidic, amphipathic with a hydrophobic region near oxidation

48
Q

What is the general structure of things metabolized by CYP2D6?

A

lipophilic amines; prefers ion-pair interactions

49
Q

Name some classes of drugs metabolized by CYP2D6

A

cardiovascular drugs, beta-adrenergic receptor blockers, tricyclic antidepressants, antipsychotics, SSRIs, H1-blockers, opioids

50
Q

What inhibits CYP2D6?

A

quinidine, fluoxetine, bupropion

51
Q

Describe the specificity of CYP3A4

A

low substrate specificity

compounds that bind to CYP3A4 are structurally diverse

52
Q

Name some things that are metabolized by CYP3A4

A

macrolide antibiotics, antiarrhythmics, benzodiazepines, immune modulators, HIV antivirals, antihistamines, calcium channel blockers, HMG CoA reductase inhibitors, and many others

53
Q

CYP3A4 is inhibited by?

A

HIV antivirals, clarithromycin, itraconazole, ketoconazole, saquinavir etc

54
Q

CYP3A4 is induced by?

A

barbituates and HIV antivirals

55
Q

Name some other phase I enzymes besides the CYPs

A 
Flavin-containing monooxygenase
Alcohol dehydrogenase
Monoamine oxidase
Esterase
Amidase
Epoxide hydrolase
56
Q

What do Phase II reactions do?

A

couple drug or activated drug (by phase I reactions) with conjugates (typically polar groups)
bioinactivate and detoxification typically

57
Q

Most dominant phase II enzymes

A

UGTs

uridine 5’-diphosphate [UDP]-glucuronosyl transferases

58
Q

Many functional groups can form glucuronide conjugates, why don’t you name some important ones?

A

O-glucuronidation
N-glucuronidation
S-glucuronidation

59
Q

What does UGTs do?

A

conjugates glucuronic acid component of UDPGA to a drug

60
Q

What’s important about where UGT and P450 are located?

A

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
Q

What do glutathione S-transferases (GST) do?

A

glutathione conjugation for nitrosaureas, mustard-type anticancer drugs

62
Q

What do sulfotransferases metabolize?

A

steroid hormones, catecholamine neurotransmitters, phenolic drugs

63
Q

Which phase II enzyme does O-, N-, S-methylation?

A

methyltransferases

64
Q

General categories of possible external factors in drug metabolism?

A

genetic factors
physiologic factors
pharmacodynamic factors
environmental factors

65
Q

What happened when chloramphenicol was IV administered to newborns for treatment of meningitis?

A

gray baby syndrome

UGT system immature and the drug concentration reached toxic levels

66
Q

What is significant about CYP3A4/7 expression and age?

A

CYP3A4/7 expression is different pre-natal and post-natal

they have overlapping but different drug specificity and regioselectivity/reactivity profiles

67
Q

What happens to some CYPs expression profiles in the first weeks after birth?

A

displays hypervariability

68
Q

what pumps xenobiotics out of fetal circulation?

A

P-gp (P-glycoprotein)

69
Q

Describe the passage of drugs from mother to infant

A

Most xenobiotics in maternal circulation cross the placenta fairly efficiently

70
Q

What is not fully functional in a baby

A

UGT system

71
Q

Name some problems with drug metabolism and old people

A

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
Q

What diseases can significantly affect hepatic drug metabolism

A

acute and chronic liver diseases

cardiac diseases can decrease blood flow to liver

73
Q

Three types of drug metabolizers people can be

A 
poor metabolizer (PM)
extensive metabolizer (EM)
ultrarapid metabolizer (URM)
74
Q

describe consequences for poor metabolizers

A

greater potential for drug-drug interactions and adverse effects
slower bioactivation of prodrug (lower efficacy)

75
Q

describe consequences for ultrarapid metabolizers

A

greater rate of drug elimination (lower efficacy)

greater potential for generating toxic metabolites

Pharmacology Test #1 (5 decks)

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