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Pharmacology > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

What is the primary role of metabolism?

What are the effects of metabolism?

A

to inactivate and detoxify pharmalogically active drugs and xenobiotics
Def: conversion of a drug to drug metabolite

although sometimes it can activate certain inactive compounds (e.g. Prodrugs)

Drug metabolism can significantly affect the intensity and duration of a drug’s pharmacological action

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2
Q

Drugs are mostly what type of molecule? How does metabolism alter this?

A

Drug metabolism primarily converts lipophilic drugs into more hydrophilic polar metabolites

this will enhance drug excretion and elimination

most drugs are lipophilic in nature (must be to get across membrane) problem is its easy to get into cell but hard to get it out of the body so metabolism works to make it to more hydrophilic compound so its more likely to get excreted

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3
Q

Describe how the lipophilic nature of most drugs will affect its excretion in the kidney. What are the implications of this?

A

Most drugs are lipophilic and readily reabsorbed in the kidney

Lipid soluble drugs
are readily reabsorbed
in the kidney tubules
(influenced by pH, urine flow)

Unbound drug molecules
less than 20,000 Da are filtered through the glomerulus

Some drugs are actively transported into the renal tubules - back in systemic circulation can exhibit their properties, could accumulate, toxicity

Water soluble drugs
are excreted in the urine

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4
Q

What are the consequences of drug metabolism for the following? Describe if it applies to all drugs or some and provide an example when possible:

Lipophilic drug
Active Drug
Prodrug
Toxic Xenobiotic

A

Lipophilic drug —polar drug (all drugs)

Active drug —inactive metabolites (most drugs) or active metabolites (diazepam)

Prodrug — active drug metabolite

Toxic Xenobiotic —non-toxic metabolite

(changes are increasing water solubility, potential for excretion in urine or bile)

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5
Q

What is the major organ site of drug metabolism?

What other organs are involved?

A

The major organ site of drug metabolism is the liver, although the intestine also plays a major role

  • other cell types involved include skin, lung, kidney & brain
  • however, drug metabolism enzymes are expressed in essentially all cells
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6
Q

What are the subcellular sites of drug metabolism?

Where in the cell are the main enzymes found?

A

CYP450 and some other enzymes (e.g. glucucronosyltransferases) are associated with the endoplasmic reticulum

  • most other metabolic enzymes are present in the cytoplasm
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7
Q

Define first pass effect and explain this concept.

A

GI + Hepatic metabolism = FIRST PASS EFFECT

Drugs administered orally are typically absorbed in the GI tract

A number of drug metabolizing enzymes (e.g. CYP3A4) are expressed in the GI tract and can metabolize absorbed drugs

Absorbed drugs and their metabolites are then transported via the portal veins to the liver where they can undergo further metabolism

In some cases only a small fraction of administered drug reaches the systemic circulation- LOW BIOAVAILABILITY

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8
Q

Briefly describe Phase I and Phase II of drug metabolism.

A

lipophilic drug undergoes phase I to become a drug metabolite (more polar compound, less active, more active, or activity is unchanged)

then that drug metabolite (with its added functional group) will undergo Phase II in which its functional group is conjugated and it becomes a drug-conjugate (water soluble, inactive)

Drugs can be excreted in urine or bile after phase I but most are excreted after Phase II

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9
Q

What are specific Phase I reactions?

Describe the result of these reactions.

A
  • Oxidation, Reduction, Hydrolysis reactions
  • Introduces (or unmasks) a small functional group on the drug e.g. –OH
  • Converts drug to a more polar metabolite
  • Alters the function of a drug (decreased, increased, unchanged)
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10
Q

Describe phase II.

A
  • Conjugation reactions introduce a large highly polar endogenous functional group onto the drug metabolite
    e. g. glucuronic acid, sulfuric acid, acetic acid, amino acid
  • Conjugation often occurs via the functional group created by Phase I reactions
  • Drug-conjugates are typically inactive
  • Create a highly polar drug-conjugate (more H2O soluble)
  • Conjugation enhances drug excretion

almost exclusively the result of phase II is loss of activity (some exceptions… where phase II can result in active metabolite ex is morphine)
main process of Phase II is further inactivation of drug and ability to make drug more water soluble

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11
Q

What is an example of a drug that undergoes no metabolism, and is excreted unchanged?

A

metformin

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12
Q

What enzymes are involved in the oxidative reactions of Phase I?

A

Oxidative reactions -

approx 75% of all phase I reactions carried out by cytochrome P450 (CYP450)

others include: flavin-containing monoxygenases, monoamine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase

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13
Q

What enzymes are involved in the reduction reactions of Phase I?

A

NADPH-cytochrome P450 reductase

alpha ketoreductases

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14
Q

What enzymes are involved in the hydrolysis reactions of Phase I?

A

epoxide hydrolases

carboxylesterases

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15
Q

What type of reaction do the following carry out?

carboxylesterase, aldehyde dehydrogenase and alcohol dehydrogenase,

A

carboxylesterase- hydrolysis reaction

alcohol and aldehyde dehydrogenase - oxidative

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16
Q

Describe the cytochrome p450 enzymes

A

microsomal-mixed functional oxidases

A superfamily of enzymes involved in biosynthesis and metabolis

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17
Q

Cytochrome p450 enzymes are microsomal-mixed functional oxidases. Explain what this means.

Why are they called cytochrome p450?

A

microsomal- membrane bound enzyme located on ER

mixed function- enzyme oxidizes two substrates simulataneously

oxidase- catalyzes an oxidation-reduction reaction involving O2

cytochrome p450- contains an oxygen binding heme group, pigment purified from liver with characteristic 450nm absorption peak in the presence of carbon monoxide

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18
Q

What purpose does the heme group in cytochrome p450 enzymes serve?

A

Contains an iron-containing heme cofactor to facilitate transfer of molecular oxygen to drug substrate

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19
Q

The cytochrome p450 superfamily are involved in biosynthesis and metabolism.

What kind of substrates do they metabolize?

How are they involved in biosynthesis?

A
  • oxidize both xenobiotics, drugs and endogenous substrates

- some CYP enzymes involved in steroid, bile acid & prostaglandin biosynthesis

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20
Q

How many genes are there for CYP450 super family?

A

57 functional genes- organized into 18 families and 44 sub families

NOMENCLATURE: CYP3A4- family 3, subfamily A, gene #4

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21
Q

Where are cyp450 expressed at the highest levels? Where are they present in lower levels?

A

Expressed at highest levels in the liver and also in the GI tract

  • lower level expression in lung, kidney, CNS and other tissues
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22
Q

In humans, 12 CYPs are responsible for metabolism of essentially all xenobiotics and drugs, what are they?

A

CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5

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23
Q

What are the most active enzymes for drug metabolism?

A

Most active enzymes for drug metabolism are the CYP2C, CYP2D and CYP3A sub families

  • CYP3A4 represents 30% of all CYP450 enzymes in the liver and accounts for the metabolism of greater than 50% of clinically used drugs
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24
Q

Describe/draw out the CYP450 reaction. What is required?

A

CYP450 reactions require:

Drug substrate

Molecular oxygen – binds to the Fe3+-heme group in CYP450 before transfer to drug

NADPH – cofactor responsible for donating electrons to reduce molecular oxygen

NADPH-CYP450 oxidoreductase- enzyme that catalyzes electron transfer from NADPH to cyp450

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25
Q

CYP450 are promiscuous enzymes. Explain what this means.

A

can metabolize multiple structurally distinct chemicals

A single compound can be metabolized by multiple CYP450 enzymes (different rates)

e.g. Citalopram is metabolized by 3A4, 2C19 and 2D6

Typically, most drugs are metabolized by one or a few enzymes (limiting redundancy)

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26
Q

CYP450s can metabolize a single drug at multiple different positions on the molecule. Give an example.

A

3A4 catalyzes both hydroxylation and N-demethylation of Clarithromycin

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27
Q

A single CYP450 can catalyze multiple different chemical reactions. Give an example.

A

CYP3A4 – hydroxylation, N-demethylation, epoxidation, N-,O-dealkylation and N-, S-oxidation

28
Q

Lipophilic drugs that have undergone a Phase I reaction contain a polar functional group. What are examples of possible polar functional groups?

A

OH, COOH, NH2

  • drug metabolite may still be pharmaceutically active
  • may not be sufficiently water soluble to allow for efficient excretion
29
Q

What drugs may directly undergo Phase II metabolism without prior phase I metabolism?

A

Some parental drugs that contain –OH, -COOH or –NH2 functional groups can directly undergo Phase II metabolism without prior phase I metabolism

ex: morphine and isoniazid

30
Q

Is the catalytic rate in phase I or phase II reactions faster?

A

catalytic rate is significantly faster in Phase II than Phase I enzymes

31
Q

Where do Phase II reactions take place? What is the exception?

A

reactions take place in the cytoplasm
(exception glucucoronidation on ER membrane)

creates a highly polar drug-conjugate

  • drug-conjugate is more water soluble and unable to freely diffuse across membranes
  • enhances drug elimination in either the URINE or BILE
32
Q

In most cases Phase II reactions inactivate drug activity; what are two exceptions?

A

minoxidil morphine

33
Q

Phase II reactions involve the transfer of a large polar molecule to the drug metabolite. Therefore, what do they require?

A
  • the drug substrate with suitable functional group
  • a specific enzyme
  • an “activated high energy” cofactor/co-substrate e.g. UDP-glucuronic acid
34
Q

What reaction is the most frequent and important of the phase II reactions?

A

Glucuronidation

(takes place on ER not cytoplasm like most other Phase II reactions)

  • promotes excretion in both urine and bile
35
Q

What are the 5 phase II reactions and what enzymes carry them out?

A

glucuronide conjugation - UDP- glucuronosyltransferase (UGT)

Glutathione conjugation - Glutathione S-transferase (GST)

Sulfate conjugation - Sulfotransferase (ST)

Acetylation - N-acetyltransferase (NAT)

Methylation - Methyltransferase (MT)

36
Q

What are prodrugs? Give four examples.

A

Prodrugs are inactive compounds that are metabolized in the body to their active forms

e.g. Carbamazepine, Irinotecan, Codeine, Prednisone

37
Q

Describe how metabolism of prodrugs alter their activity.

A

Metabolism of the prodrug results in the formation of the pharmaceutically active metabolite

The active metabolite is ultimately inactivated by further metabolism

Useful when the prodrug has a better pharmacokinetic profile than its active metabolite
e.g. solubility, absorption, stability, toxicity etc. etc.

38
Q

If an enzyme undergoes metabolism by carboxylesterase, what phase/type of reaction has taken place?

A

phase I hydrolysis

39
Q

What organ is primarily responsible for drug excretion? Describe this process?

A

The KIDNEY accounts for the excretion of most drugs. Unbound water soluble polar drug metabolites are
either filtered or actively secreted into the proximal tubules and excreted in the URINE

40
Q

The KIDNEY accounts for the excretion of most drugs. Where else are drugs excreted and when might they be excreted in this manner?

A

Some drugs and their metabolites are excreted in the BILE (Mr >300 Da with both polar and lipophilic groups)

Drugs are actively transported into the bile and stored in the gallbladder before release into the GI tract

41
Q

Describe how enterohepatic drug recirculation influences the elimination and
pharmacokinetic parameters of drugs that are excreted in the bile.

How is clearance, half life, and AUC effected?

A

When food enters the small intestine, a hormone called cholecystokinin is released, signaling the gallbladder to contract and secrete bile into the small intestine through the common bile duct.

Only a fraction of drug excreted in bile will actually be eliminated in the feces, as bacterial enzymes in the GI tract can hydrolyze drug-conjugates allowing for drugs to be reabsorbed and enter the circulation again where they undergo further hepatic metabolism.

This can reoccur until the drug is either completely inactivated or excreted by the kidney or bile

Can significantly prolong pharmacological effect of drugs by reducing clearance, extending half life and increasing plasma exposure (AUC)

42
Q

Interactions between drugs can occur when an individual is co-administered two or more drugs
The presence of one drug may affect the metabolism of another drug leading to changes in drug concentrations that can lead to:

  • Adverse effects and Toxicity
  • Changes in therapeutic efficacy

By what two principal mechanisms might a drug affect the metabolism of other drugs?

A
  • Induction of CYP450 enzymes

- Inhibition of CYP450 enzymes

43
Q

What drugs will induce expression of specific CYP450 enzymes?

A

rifampin, phenytoin, phenobarbital, carbamazepine and St. John’s wort all induce 3A4

Phenobarbital, Rifapin, and carbamazepine also induce 2C9 and 2C19

44
Q

By what mechanism can certain drugs induce the expression of specific CYP450 enzymes?

A

Inducing drugs serve as ligands for specific transcription factors that promote the increased
transcription of specific CYP450 genes

45
Q

What is the result of CYP450 induction by certain drugs?

A

Increases metabolism of the CYP450 enzyme substrates

  • Decreases drug activity (Increases in the case of a prodrug)
  • Increases drug clearance
  • Can reduce drug concentration below a critical therapeutic dose and result in treatment failure
46
Q

How can drugs reversibly inhibit a CYP450 enzyme? Irreversibly?

A

REVERSIBLE: Competitive or allosteric

-IRREVERSIBLE: Suicide inhibitor (covalent binding)

47
Q

How will inhibitors of CYP450 enzymes affect drug metabolism. Explain how drugs with a narrow therapeutic window may be affected.

A

Inhibitors decrease drug metabolism resulting in an increase in the concentration of drug

  • potential for toxicity- especially with drugs that have a narrow therapeutic window!
48
Q

What are some examples of inhibitors of CYP450 isozymes?

A 
fluconazole (M)
ketoconazole (S)
Itranaconazole (S)
Ritonavir (S)
Erthyromycin (M)
Clarithromycin (S)
Grapefruit juice (S)
omeprazole

these inhibit 34A

49
Q

Describe how grapefruit juice consumption can affect the metabolism of certain drugs.

A

CYP3A4 is expressed in the GI tract and metabolizes drugs during the absorption process -decreasing their bioavailability (part
of the first pass effect)

Grapefruit juice contains compounds (e.g. naringin & furanococoumarins) that inhibit CYP3A4 activity

These compounds inhibit 3A4 in enterocytes, thereby decreasing 3A4 metabolism of drug in the GI tract (No effect on hepatic CYP3A4)

As a result more drug reaches the liver and ultimately the systemic circulation

  • Increasing drug bioavailability
  • increase potential therapeutic effect
  • increased potential for ADVERSE EFFECT
50
Q

Cyclosporin is a 3A4 substrate and immunosuppressant drug used to prevent organ rejection.

A transplant patient acquires TB and is prescribed Rifamin.

Describe the consequences.

A

Rifampin is a 3A4 inducer and anti-TB drug;

  • Rifampin induces 3A4 expression
  • Increased expression of 3A4 increases the metabolism of cyclosporin
  • reduced levels of cyclosporin increases the risk of organ rejection
51
Q

Clopidrogel is a 2C19 substrate and antiplatelet drug (prodrug) that inhibits blood clotting.

If a patient is prescribed Rifampin alongside Clopidrogel, describe the outcome.

A

Rifampin is a 2C19 inducer;

Consequence -Rifampin induces 2C19 expression

  • increased 2C19 increases the metabolism of the clopidrogel prodrug
  • increased activation of clopidrogel increases risk of bleeding
52
Q

Cyclosporin is a 3A4 substrate and immunosuppressant drug with concentration-dependent nephrotoxicity.

Describe the outcome of interaction with Itranaconazole.

A

Itranaconazole is a potent 3A4 inhibitor and anti-fungal agent

Consequence -Itranaconazole inhibits activity of 3A4

  • reduced 3A4-mediated metabolism of cyclosporin
  • cyclosporin levels increase
  • increased potential for cyclosporin-mediated nephrotoxicity
53
Q

Lopinavir is a 34A substrate and anti-HIV protease inhibitor. It has extensive first pass effects which limit its use; its difficult to achieve effective therapeutic levels.

What drug could you prescribe alongside to increase its effects?

A

Ritonavir is a potent 3A4 inhibitor
anti-HIV protease inhibitor
-significant GI adverse effects limit its clinical use

Low does of ritonavir has no GI effects but potently inhibits 3A4

  • decreases first pass metabolism of Lopinavir “Boosting” its levels
  • enhanced anti-HIV effect
54
Q

Describe how the following factor can affect drug metabolism:

Age (neonates and elderly)

A
  • Neonates vs Geriatrics- differences in enzyme expression levels
  • decreased activity of Phase I metabolism in the elderly (approx 30-40%)-dose reduction
  • conjugating enzyme deficiency in infants leads to gray baby syndrome in infants given chloramphenicol- caused by build up of a chloramphenicol oxidation metabolite resulting in circulatory collapse and cyanosis
55
Q

Describe how the following factor can affect drug metabolism:

Pregnancy

A
  • the activity of some enzymes increase (2C9, 2D6 & 3A4), while others decrease (1A2 & 2C19)
56
Q

Describe how the following factor can affect drug metabolism:

Race and ethniciy

A
  • different races and ethnic groups express different polymorphic variants
  • exhibit different responses to drugs
57
Q

Describe how the following factor can affect drug metabolism:

grapefruit juice 
(How does it affect 3A4 and bioavailablity and half-life?
A

grapefruit juice inhibits intestinal 3A4 not hepatic 3A4

affects bioavailability NOT half life

A single 8oz glass can inhibit 3A4 for 24-48 hrs

58
Q

Describe how the following factor can affect drug metabolism:

grapefruit juice 
(How does it affect 3A4 and bioavailablity and half-life?
A

grapefruit juice inhibits intestinal 3A4 not hepatic 3A4

affects bioavailability NOT half life

A single 8oz glass can inhibit 3A4 for 24-48 hrs

59
Q

Describe how the following factor can affect drug metabolism:

St John’s wort

A

St. John’s wort a herbal medication induces CYP3A4 expression

60
Q

Describe how the following factor can affect drug metabolism:

chemicals in cigarette smoke, charbroiled food and cruciferous vegetables

A

chemicals in cigarette smoke, charbroiled food and cruciferous vegetables all induce CYP1A2 (approx 3 fold)

smokers sometimes need higher doses of certain drugs metabolized by CYP1A2 e.g. theophylline (Asthma/COPD), some antidepressants

61
Q

Describe how the following factor can affect drug metabolism:

alcohol

A

chronic alcohol induces expression of CYP2E1

62
Q

Describe how the following factor can affect drug metabolism:

pollutants and xenobiotics

A
  • a number of pollutants and xenobiotics are also known to induce specific CYP450 enzymes
63
Q

Describe how the following factor can affect drug metabolism:

Disease

A
  • diseases that effect the liver or blood flow to the liver (e.g. cardiac disease)
  • inflammatory cytokines decrease expression of many CYP450 isoforms
64
Q

Describe how the following factor can affect drug metabolism:

Metabolic drug interactions

A
  • CYP450 induction and inhibition can affect drug toxicity/efficacy
  • some drugs induce the enzyme responsible for their own metabolism, reducing
    levels of active drug over time (Pharmacokinetic tolerance) e.g. Carbamazepine
65
Q

Describe how the following factor can affect drug metabolism:

interactions between drugs and endogenous compounds

A

some drugs may compete for the same endogenous conjugation substrate

66
Q

Describe how the following factor can affect drug metabolism:

Genetics

A
  • many of the enzymes involved in drug metabolism are polymorphic
  • individuals express different enzyme alleles with different activities and expression
  • results in individual-individual differences in the efficiency of drug metabolism and drug responses

Pharmacology (13 decks)

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