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Pharm > Drug metabolism > Flashcards

Drug metabolism Flashcards

1
Q

site of highest amount of drug metabolism

A

Liver (sER)

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2
Q

Sites of drug metabolism

A

Liver, GIT, Lungs, Kidney, Brain, Skin

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3
Q

Oral bioavailability

A

fraction of total dose that reaches systemic circulation

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4
Q

Bioavailability is influenced by… (4)

A

Solubility

Membrane Permeability

P-gp efflux

Presystemic first pass metabolism

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5
Q

Significance of P glycoprotein in metabolism of drugs (example given in class)

A

P glycoprotein is upregulated in some tumors –> difficulty in delivery/metabolism of drug

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6
Q

Number and description of phases of drug metabolism

A

Phase 1 = Chemical mod (biotransformation) – Oxidation, Hydroxylation, etc. Introduces a new functional group or expose a functional group for next phase rxn.

Phase 2 = Conjugation with a polar group (acetyl, sulfate, glucuronide, etc)

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7
Q

Name three things influenced by drug metabolism

A

Pharmacological activity

Half life

Side effects

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8
Q

Termination of xenobiotic action involves…

A

Bioinactivation

Detoxification

Elimination

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9
Q

Bioinactivation

A

Active site affinity for metabolites are frequently much lower than the parent compound

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10
Q

Procaine undergoes bioinactivation into what two compounds

A

p-amino benzoic acid

diethyl aminoethanol

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11
Q

Detoxification:

Example?

A

The metabolites may be less active or completely inactive

Chlorpyrifos to diethylphosphate and 3,5,6-trichloro-2-pyridinol

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12
Q

Elimination: In general, metabolism ____________ of drog molecules

A

increases the polarity

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13
Q

What effects do increased polarity have on a drug?

A

Decrease lipid solubility/ increase water solubility

Increases ability to excrete drug

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14
Q

Prodrugs =

example?

A

Drug metabolites may be more active than the parent compound, or the parent compound may require activation for biological activity

tamoxifen –> 4-hydroxytamoxifen

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15
Q

Example of Toxification (genotoxicity)

A

Polyaromatic hydrocarbons

benzopyrene undergoes epoxidation/hydrolysis to form a stable expoxide, which is highly reactive. Intercalates into DNA and becomes mutagenic.

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16
Q

Most adverse reactions related to drug metabolism are _______.

Why?

A

idiosyncratic (unpredictable)

  1. They cause protein modification/replacement. These interactions are poorly understood.
  2. Risk factors vary from patient to patient, influencing the predictability of metbolite behavior.
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17
Q

The most frequent reason that new agent is not approved by the FDA

A

Drug induced hepatic damage

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18
Q

Three metabolic pathways for APAP

A
  1. Glucuronidation (45-55%)
  2. Sulfation (sulfate conjugation) accounts for 20–30%
  3. N-hydroxylation and dehydration, then GSH conjugation (less than 15%)
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19
Q

The problem with APAP

A

THe formation of N-acetyl-p-benzoquinoneimine (NAPQI), which contains bonds that are highly reactive with sulfahydryls.

–> NAPQI is irreversibly conjugated with the sulfhydryl groups of glutathione, which causes oxidative stress to the cells.

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20
Q

Formation of NAPQI is mediated by what enzyme

A

Cyochrome P450

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21
Q

Phase 1 reactions are usually _________, but others may occur too (ex. ___ and ____)

A

usually oxidation

others ex. reduction, hydrolysis, etc.

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22
Q

Phase 1 reactions usually use what enzyme and substrate?

A

Enzyme = cytochrome P450

Substrates = NADPH and Oxygen

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23
Q

Metabolites are excreted if ________

..or they are ____________

A

sufficiently polar

functionalized to undergo phase2 reaction

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24
Q

Structure of the cytochrome P450 enzymes

A
  • Embedded in the ER membrane
  • Substrate entrance near the membrane
  • Product exit site above
  • Contains HEME group
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25
Q

2 domains of the Cyt. P450 system

A

P450 reductase - where FAD and FMN transfer electrons to make available for reaction

P450 domain = contains the HEME group which accepts the 2e- from FMN to form ROH + H20

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26
Q

Overall P450 system

A

NADPH 2e- -> (FAD -> FMN) -> (HEME) –> ROH + H20

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27
Q

Other potential protein involved in electron transfer to p450

A

Cytochrome b5

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28
Q

Family and subfamily homology in CYPs

A

Family = >40%

Subfamily = >55%

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29
Q

How many CYP450 enzymes in humans?

A

57

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30
Q

1/3 of all drugs are metabolized by ________

A

Cyp3A4

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31
Q

1/5 of all drugs are metabolized by

A

CYP2D6

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32
Q

CYPS contain a _____ that is active site

A

Catalytic center

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33
Q

The active site of CYP contains …

A

iron-heme cofactor

  • the iron is coordinated to:
    • four nitrogen atoms of the heme
    • one thiolate ligand derived from cysteine
    • (in the native state) to a water molecule
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34
Q

Max light absorption of the catalytic center of CYP450 is called ______ and is ______

A

Soret peak

450nm

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35
Q

Draw the reaction mechanism for the active site of CYP

A
  1. Ferric
  2. Ferric low spin
  3. Ferric high spin
  4. Ferrous
  5. Ferric hydroperoxide
  6. Oxyferryl, Compound I

DRAW THIS OUT

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36
Q

Hydroxylation in the CYP process

A

Homolytic breakage of bond to form 2 radicals (carbon-centered radical)

H binds to Oxygen

OH leave the heme to attach back to the carbon (forms ROH and a Ferric iron state)

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37
Q

6 other reactions catalyzed by CYPs

A
  1. aromatic hydroxylation
  2. N-dealkylation
  3. O-dealkylation
  4. N-oxidation
  5. Sulfoxidation
  6. Deamination
38
Q

What effects does intrinsic factors have on catalysis of reactions by CYPs?

A
  • Topography of protein binding site
  • Steric hiderance of access to the catalytic heme group

….both affect the ability to catalyze reactions

39
Q

Reversible inhibition - how does it work?

A

compete with other substrates for occupancy of active site of the same CYP

40
Q

3 Factors that determine binding strength in reversible inhibiton?

A

Coordination strength with heme iton

Hydrophobic contacts with binding site of CYP

Specific contacts (e.g. H bonds) with binding site residues

41
Q

What kind of molecules have a stronger affinity for the heme iron?

A

Molecules with a nitrogen as 6th iron-coordinating ligand (stronger than those with oxygen or carbon)

42
Q

Big example of CYP inhibiton?

A

Azo antifungal drugs are strong inhibitors of CYPS?

(ketoconazole)

43
Q

What situation of inhibition was erythromycin given as the example?

A

A case in which the metabolite, not a substrate, acts as the inhibitor

44
Q

Inhibition may not inhibit metabolism of all substrates of specific CYP - example of this? What kind of inhibition is this example?

A

Cimetidine inhibits warfarin metabolism but not ibuprofen (CYP2C)

Competitive inhibition!

45
Q

What is MBI?

Two examples of this?

A

mechanism based inhibition (suicide inhibition)

Metabolism of substrate makes a reactive metabolite that irreversibly interacts with the heme or residues in the binding site

  • 17a - acetylenic estrogen
  • halocarbons
46
Q

Significance of MBI

A

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

47
Q

What happens when small molecule inhibition blocks access to the active site?

A

Enzyme is effectively dead and must be turned over and replaced

48
Q

Example of induction? What happened?

A

Alfentanil given with ketoconazole, rifampin, or grapefruit juice

  • Ketoconazole and grapefruit juice increased the amount of Alfentanil
  • Rifampin greatly reduced it
49
Q

Why does rifampin affect drug levels in the body?

A

it is a strong inducer of CYP genes, which will result in greater clearance of the molecule and drastically shortened half-life.

50
Q

In induction, there is significant _______ between molecules, proteins, and the CYPs that they upregulate

A

cross-talk

51
Q

______ play a role in detecting xenobiotics and upregulating CYPs in response

A

transcription factors

52
Q

____ is reacts with Polycyclic aromatic hydrocarbons to form reactive metabolites that result in _________

A

Cyp 1A1

toxicity

53
Q

Example of cooperativity?

A

Fluvastatin and Flurbiprofen

Fluvistatin interferes with the hydroxylation reaction of flurbiprofen

54
Q

Dapsone and flurbiprofen relationship

A

When dapsone is bound to the active site, flurbiprofen metabolism is increased, reducing half life and effective time

55
Q

about ___% of all drug-drug interactions involve ___

A

50%

involve CYPs

56
Q

DDI happens when the ___ or ___ is altered by coadminstration of another drug, food, or chemical

A

efficiency or toxicity

57
Q

What types of drugs are particularly susceptible to DDIs in multidrug therapies

A
  • High first pass metabolism
  • narrow therapeutic index
  • Steep dose-response relationship
58
Q

Example given for DDI

A

Lopinavir and Ritonavir

Both bind to Cyp3A4

  • Lopinavir = Substrate
  • Ritonavir = inhibitor
59
Q

Felodipine?

A

Its a CCB that was given with ethanol and grapefruit juice

= Substrate of CYP3A4

It was increased significantly when given with the juice

60
Q

What does grapefruit juice contain that causes its effects on drugs

A

Bergamottin = MBI of Cyp3A4

Naringin = Competitive inhibitor of Cyp3A4

(6,7 dihydroxybergamottin)

61
Q

CYP1A1/2 contains a _______ that results in its specificity for _______

A

narrow binding site

planar molecules

62
Q

CYP1A2 substrates and inhibitors

A

Substrates

  • Caffeine
  • Propranolol
  • Clozapine
  • Tacrine

Inhibitors

  • Fluvoxamine
  • Ciprofloxacin
63
Q

CYP2A6 metabolizes…

A
  • Coumarin
  • nicotine
  • aflatoxin B1
  • Naproxen
  • tacrine
  • clozapine
  • mexiletine
  • cyclobenzaprine
64
Q

CYP2A6 bioactivates

A

nitrosamines and procarcinogens

65
Q

CYP 2C metabolizes…

A

20-25% of clinically important drugs

66
Q

CYP2C8

A

mainly expressed in extrahepatic tissues

Metabolizes tricyclics

(2c8 so you can feel great)

67
Q

CYP2C19

A

Metabolizes basic compounds, frequently containing C=O or S=O groups

also antiepileptics and PPIs

(19y.o.’s are so basic)

68
Q

CYP2C9

A

most important member of the 2C family

Neutral/acidic, amphipathic with a hydrophobic region near oxidation

  • Substrates* = Sulfonylureas, most NSAIDs, Warfarin, Losartan (Angiotensin 2 receptor blockers)
  • Inhibitors* = Amiodarone + Fluconazole
69
Q

CYP2D6

A

20% of drugs, only 3% of liver isozymes

Weakly inducible by rifampin and Dex

Metabolizes lipophilic amines, prefers ion-pair interactions

  • CV drugs (quinidine is also inhibitor)
  • Beta blockers
  • Tricyclics
  • Antipsychotics
  • SSRI
  • H1 blockers
  • Opioids

*inhibited by quinidine, fluoxetine, buproprion

70
Q

CYP3A4 ligands

A
  1. Acetaminophen
  2. Alprazolam
  3. Amiodarone
  4. Buspirone
  5. Clotrimazole
  6. Colchicine
  7. Dapsone
  8. Dextromethorphan
  9. Estradiol (b)
  10. Ketoconazole
  11. Lidocaine
71
Q

CYP3A4

A

half of all drugs

low substrate specificity

Metabolizes: macrolides, antiarrhythmatics, benzos, HIV antivirals, antihistamines, CCBs, HMGCoA Reductase inhibitors

Inhibited by: HIV antivirals, clarithromycin, itraconazole, ketoconazole

72
Q

Other phase 1 enzymes

A
  • FMN
  • Alcohol dehydrogenase
  • MAO
  • Esterase
  • Amidase
  • Epoxide Hydrolase
73
Q

Phase 2 drug metabolism involves

A

addition of very polar groups to an added or preexisting functional group

74
Q

Typically, phase 2 reactions _______ and ________ compounds

A

bio-inactivate and detoxify

  • But bioactivation occurs! (Morphine -> 6->glucuronide)*
  • and toxification! (carcinogenicity, allergic rxns)*
75
Q

Top three contributors for Phase 2 reactions

A

UGTs

SULTs

GSTs

(NAT, TPMT, Others)

76
Q

Why are UGT most important phase 2 enzymes?

A

(UDP glucuronosyl transferases) are most important because…

  1. Readily available supply of glucose and UTP in liver
  2. Will react in 4 rxns to UDP-Gluc.Acid
  3. Many functional groups can conjugate to GA
    1. O-Glucuronidation
    2. N-Glucuronidation
    3. S-Glucuronidation
77
Q

UGT is spacially colocalized with _____ at the _______.

A

P450 at the ER membrane

(This allows the phase 1 metabolite to be hit by UGT without having to travel a long path)

78
Q

SULT works on ….(3)

What does it use?

A
  1. steroid hormones
  2. catecholamines
  3. phenolic drugs

The reaction uses PAPS –>PAP

(3 PhosphoAdenosine 5 PhosphoSulfate)

79
Q

Glutathione conjugation by _______________ …..e.g. for….

A

Glutathione S-transferase

for:

  • nitrosaureas,
  • mustard-type anticancer drugs
80
Q

External factors to drug metabolism

A
  1. Genetics (race or personal variation)
  2. Physiologic factors (Disease, gender, nutrition, age)
  3. Pharmacodynamic factors (dose, freq)
  4. Environmental factors (CYP competition, poisioning, induction)
81
Q

Sulfated drugs are ____ and ____________, as well as have reduced _________

A

more hydrophillic and easier to excrete

reduced activity in system

82
Q

Babies have an immature ______ system

A

UGT

(Grey baby, chloramphenicol case study)

83
Q

_____ expression is different pre/post natally

How similar are they?

A

CYP3A4 and 3A7

– they have different but overlapping drug specificities and regioselectivity/reactivity profiles

84
Q

Women ingest an average of ___ drugs during pregnancy

A

10

85
Q

most xenobiotics in maternal circulation ___________

A

cross the placenta

86
Q

Elderly patients have higher incidence of ___

Three other metabolic changes/effects in older patients

A

DDI’s

  • Decreased first pass metabolism due to reduced hepatic bloodflow
  • Decreased hepatic mass reduces phase 1 reactions (slightly)
  • Decreased renal flow = reduced clearance
87
Q

Cirrhosis and CV diseases can both…

A

negatively impact metabolism or hepatic clearance

88
Q

Atypical metabolizers include

A

Poor metabolizers

Extensive metabolizers

Ultrarapid metabolizers

89
Q

Poor metabolizers have a greater potential for

A

DDIs and sides (also have slower bioactivation = lower efficacy)

90
Q

Ultrarapid metabolizers have greater

A

rate of elimination

potential for generating toxic metabolites!

91
Q
A

Pharm (4 decks)

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