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PT 1 > L5 Drug Metabolism > Flashcards

L5 Drug Metabolism Flashcards

1
Q

What is the enzymatic catalyzed conversion of a drug or xenobiotic compound to their metabolites?

A

Metabolism

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2
Q

Drug metabolism primarily converts ___ drugs into more ___ metabolites.

A

Lipophilic; hydrophilic, polar

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3
Q

Most drugs are ___ and are readily reabsorbed in the ___.

A

Lipophilic; kidney

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4
Q

What are the two general consequences of drug metabolism?

A
  1. Increasing water solubility

2. Increased potential for excretion in urine or bile

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5
Q

What is the major site of drug metabolism and 5 other minor sites?

A
  1. Liver
  2. Intestine
  3. Skin
  4. Lung
  5. Kidney
  6. Brain
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6
Q

True or false - drug metabolism enzymes are expressed in about half of all cells.

A

False - they are expressed in essentially all cells

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7
Q

CYP450 and some metabolic enzymes are associated with the ___. Most other metabolic enzymes are present in the ___.

A

ER; cytoplasm

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8
Q

GI + Hepatic metabolism = ?

A

First pass Effect

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9
Q

What types of reactions occur in Phase I?

A

Oxidation, reduction, hydrolysis

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10
Q

What happens to the lipophilic drug in Phase I of metabolism?

A

Introduction/unmasking of a small function group that converts the drug into a more polar metabolite

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11
Q

What types of reactions occur in Phase II?

A

Conjugation reactions

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12
Q

What happens to the drug metabolite in Phase II?

A

Introduction of a large, highly polar endogenous functional group onto the drug metabolite; often occurs via the functional group created by Phase I reactions

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13
Q

What class of enzymes functions in 75% of all Phase I reactions?

A

CYP450

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14
Q

Where are CYP450 enzymes located?

A

Bound to the membrane of the ER

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15
Q

Why are CYP450 enzymes called “mixed function”?

A

The enzyme catalyzes a reaction in which two substrates are oxidized simultaneously (drug and the NADPH cofactor)

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16
Q

The most active enzymes for drug metabolism come from which three sub families?

A

CYP2C, 2D, and 3A

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17
Q

What are the four requirements for CYP450 reactions?

A
  1. Drug substrate
  2. Molecular oxygen
  3. NADPH
  4. NADPH-CYP450 oxidoreductase
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18
Q

True or false - there is one CYP enzyme for every structurally distinct chemical.

A

False - a single compound can be metabolized by multiple CYP450 enzymes and vice versa

19
Q

What are the two major reason we need Phase II metabolism?

A
  1. Drug metabolite may still be active

2. Drug metabolite may not be sufficiently water soluble to allow for efficient excretion

20
Q

Which Phase has a faster catalytic rate?

A

Phase II (slightly)

21
Q

Where do Phase II reactions occur?

A

Cytoplasm (except glucuronidation)

22
Q

What is required for a Phase II reaction?

A
  1. Drug substrate with a suitable functional group
  2. Specific enzyme
  3. Activated high energy co-factor or co-substrate
23
Q

What is the most frequent and most important of the Phase II reactions?

A

Glucuronidation

24
Q

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

A

Prodrugs

25
Q

The ___ accounts for the excretion of most drugs.

A

Kidney

26
Q

In addition to the urine, some drugs and their metabolites are excreted in the ___.

A

Bile (larger molecular weight with polar and lipophilic groups)

27
Q

What process can significantly prolong pharmacological effects of drugs and why?

A

Enterohepatic recirculation; enzymes in the GI tract can hydrolyze drug-conjugates, allowing for reabsorption and re-entry into circulation; this process reduces clearance, extends half-life, and increases plasma exposure

28
Q

What are the two principle mechanisms by which drugs affect the metabolism of other drugs?

A
  1. Induction of CYP450 enzymes (enhances metabolism, decreases drug activity except in the case of a prodrug, increases drug clearance)
  2. Inhibition of CYP450 enzymes (decreases metabolism, increases drug activity except in the case of a prodrug, decreases drug clearance)
29
Q

What drugs/xenobiotics are known to induce the expression of CYP450 enzymes?

A
  1. Rifampin
  2. Phenytoin
  3. Phenobarbital
  4. Carbamazepine
  5. St. John’s Wort
30
Q

How do drugs induce CYP450 enzymes?

A

They serve as ligands for specific TFs that promote increased transcription of CYP450

31
Q

How do drugs inhibit CYP450 enzymes?

A

Bind to drug receptor on CYP450

32
Q

___ increases the bioavailability of drugs metabolized by CYP3A4 in the Gi tract.

A

Grapefruit juice

33
Q

How does grapefruit juice affect metabolism?

A

Contains compounds that inhibit CYP3A4 activity, which decreases metabolism and increases drug bioavailability, potential therapeutic effect, and potential for adverse effects

34
Q

What is a major 3A4 inducer?

A

Rifampin (anti-TB drug)

35
Q

How does rifampin affect cyclosporin?

A

Rifampin induces 3A4 expression, increasing metabolism of cyclosporin (immunosuppressant drug), which reduces levels of cyclosporin and increases risk of organ rejection

36
Q

How does rifampin affect clopidrogel?

A

Rifampin induces 2C19 expression, increases metabolism of clopidrogel, an anti-platelet prodrug, which increases activation of clopidrogel and increases risk of bleeding

37
Q

What are two potent 3A4 inhibitors?

A

Itranaconazole and Ritonavir

38
Q

How does itranaconazole affect cyclosporin?

A

Itranaconazole inhibits 3A4 activity, leading to reduced metabolism of cyclosporin, increase in cyclosporin levels and increased risk for nephrotoxicity

39
Q

How does ritonavir affect lopinavir?

A

Lopinavir is an anti-HIV inhibitor with extensive first pass effect; ritonavir has the same therapeutic effects but with bad GI effects; a low dose of ritonavir inhibits 3A4, decreases first pass metabolism of lopinavir, boosts its levels and its effects

40
Q

What are some factors affecting drug metabolism?

A
  1. Age
  2. Pregnancy
  3. Race and ethnicity
  4. Diet and environment
  5. Disease
  6. Metabolic drug interactions
  7. Interactions with endogenous compounds
  8. Genetics
41
Q

How is Phase I metabolism affected in the elderly?

A

Decreased (30-40%)

42
Q

What enzymes increase in pregnancy? What enzymes decrease?

A

Increase: 2C9, 2D6, 3A4
Decrease: 1A2, 2C19

43
Q

Chemicals in cigarette smoke, charbroiled food, and cruciferous vegetables all induce ___.

A

CYP1A2

44
Q

Chronic alcohol use induces expression of ___.

A

CYP2E1

PT 1 (34 decks)

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