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Pharmacokinetics > Exam 1 Hepatic Drug Metabolism > Flashcards

Exam 1 Hepatic Drug Metabolism Flashcards

1
Q

What is the liver anatomy and physiology?

A

liver weight is 1.5 kg and hepatic blood flow is 1.5 L/min

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2
Q

Where do absorbed drugs go?

A

all drugs are absorbed in the small intestine and go through the portal vein → then to the liver for elimination/metabolism → then to system circulation

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3
Q

What is the blood flow like in the liver?

A
  1. blood flows out of the liver through hepatic veins into the interior vena cava
  2. bile flows out of the liver via the bile duct
  3. oxygen rich blood flows into the liver through the hepatic artery (20%)
  4. nutrient rich blood coming from the bowel flows into the liver via portal vein (80%)
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4
Q

What is bile composed of?

A

water, bile salts, bilirubin, fats

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5
Q

What is the function of bile?

A
  1. surfactants
  2. helps fat digestion
  3. bilirubin elimination (final waste product of RBC breakdown)
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6
Q

What is one of the elimination routes of bilirubin elimination?

A

bile

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7
Q

What is the blood flow like within the hepatocytes?

A

blood flows toward the central vein (portal vein → sinusoid → central vein)

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8
Q

What makes up the portal triad?

A
  1. hepatic artery
  2. bile duct
  3. hepatic portal vein
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9
Q

What is the space of disse?

A

the space between hepatocytes and endothelial cells

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10
Q

How does bile flow within the hepatocytes?

A

from the central vein and outwards → the opposite direction of blood flow!

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11
Q

What are the liver sinusoidal endothelial cells?

A
  1. make up 15-20% of liver cells

2. contain many open pores (fenestrae) with diameters from 100-150 nm

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12
Q

What are Kupffer cells (resident macrophages)?

A
  1. responsible for reticuloendothelial system (RES) → the protective system of removing large molecules in the body
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13
Q

What is the importance of sinusoidal capillaries?

A

allows large molecules to pass through the fenestrae which allows direct exchange between blood and hepatocytes

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14
Q

What are hepatocytes?

A
  1. major cell of the liver → makes up 70% of liver cells
  2. form liver’s major metabolic and functional core
  3. functions include → synthesis of plasma proteins such as albumin and coagulation factors, regulation of nutrient metabolic balance, synthesis of bile acids, detoxification of bilirubin, and detoxification of xenobiotics
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15
Q

What are the principles of drug metabolism?

A
  1. converts lipophilic compounds into hydrophilic compounds which are readily excreted in urine or bile
  2. can be divided into 4 categories based on the chemical reaction
  3. is catalyzed by a limited number of enzymes with broad substrate specificities
  4. certain drug metabolizing enzymes’ expression can be upregulated, leading to increased metabolism of drugs
  5. drug metabolizing enzymes’ activities can be inhibited by drugs
  6. gut microbiota mediates certain drug metabolism, mainly reduction and hydrolysis
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16
Q

How are lipophilic compounds made into more hydrophilic compounds to be excreted into the bile or urine?

A

Phase 1 reaction → functionalization (which adds a functional group such as OH to make it more hydrophilic)
Phase 2 reaction → conjugation (which adds a large group such as glucoronidation)

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17
Q

Metabolism accounts for how much of the drug elimination route?

A

75%

18
Q

What is the overall principle behind drug metabolism?

A

parent drug → metabolite

19
Q

What are the 4 types of reactions of drug metabolism?

A
  1. oxidation (via cytochrome P450)
  2. conjugation (UGT carries out glucouronidation)
  3. hydrolysis (carboxyesterase hydrolyzes procaine)
  4. reduction (carbonyl reductase reduces haloperidol)
20
Q

What are the two major reactions for hepatic drug metabolism?

A

oxidation and conjugation

21
Q

Hydrolysis and reduction occur where?

A

they occur in the gut by gut bacteria

22
Q

Cytochrome P450 is responsible for how much of drug metabolism?

A

about 50% → next would be UGT (11.7%) then hydrolase (10.8%)

23
Q

What is some important information to know about cytochrome P450 enzymes?

A
  1. ranks first in catalytic versatility and the number of drugs it detoxifies among different enzymes
  2. highest level of drug metabolizing P450 is found in the liver (ER) among different tissues
  3. monooxygenase → starts out with O2 and creates an alcohol and water
  4. > 50 P450 enzymes in humans but less than 10 are involved in most drug metabolism
24
Q

What is the active site of the CYP 450 enzyme?

A

the heme group

25
Q

What are the binding pockets of CYP 450 like?

A

they have large binding pockets so many different molecules can be metabolized by CYP 450 enzymes

26
Q

What are the most important CYP enzymes?

A

CYP3A4 and CYP2D6 metabolize over half the orally effective drugs in current use (CYP3A4 is the most important)

27
Q

What is CYP phenotyping using recombinant CYP protein used for?

A

to examine parent drug disappearance rate (drug is placed into vials with different CYP enzymes) → the one that shows the fastest disappearance rate will be the enzyme that is most responsible for the drug’s metabolism

28
Q

What are some reactions mediated by P450?

A
  1. aromatic hydroxylation (3A4) → adds OH onto an aromatic group
  2. aliphatic hydroxylation (2D6) → adds OH on carbon chain
  3. N-dealkylation (2D6) → removes methyl group from the nitrogen
  4. O-dealkylation (2D6) → removes methyl group from the oxygen to make a hydroxyl
29
Q

Glucuronidation is mediated by what?

A

UGT → transfers UDP from UDPGA (the cofactor) onto the drug

30
Q

What are the effect of enzyme inducing drugs?

A

enzyme inducing drugs such as rifampin activates transcription factor PXR (pregnane X receptor which is a ligand activated TF) which leads to decreased exposure to enzyme substrates such as triazolam → leads to increased metabolism of drugs

31
Q

What does ketoconazole do?

A

binds to CYP3A4 and inhibits its enzyme activity

32
Q

What are the effect of enzyme inhibiting drugs?

A

enzyme inhibiting drugs such as ketoconazole inhibit activities of drug metabolizing enzymes, leading to increased substrate drug exposure → leads to decreased metabolism of drug

33
Q

What is the gut microbiota?

A
  1. a collective term for the microorganisms in the human gut
  2. outnumber human cells by 3 times
  3. gene pool size 100 times larger than human genome size
  4. more and more bacteria as you move down the GI tract (pH increases, antimicrobials decreases, oxygen decreases)
34
Q

What happens with prontosil reduction by gut bacteria?

A

protonsil has two double bonded nitrogens and the gut bacteria reduces it to create two molecules (one inactive and one sulfanilamide) that have amines

35
Q

What happens with mycophenolate glucuronide hydrolysis by gut bacteria?

A

in the liver: MPA (an immunosuppressant) → MPA-glucuronide (via UGT) →→biliary excretion (in the intestine) changes MPA-glucuronide into MPA (via gut bacteria, specifically beta-glucuronidase)

shows enterohepatic circulation in which the second peak in the plasma concentration comes from release of MPA by MPA-glucuronide by gut bacteria

36
Q

How is irinotecan GI toxicity mediated by gut bacterial enzymes?

A

inrinotecan → SN-38 (toxic anti-cancer compound) via carboxyesterase → SN-38 glucuronide (inactive) via UGT →→ biliary excretion→→SN-38 via gut bacterial beta-glucuronidase → dose limiting diarrhea (in intestine)

37
Q

What is the main mechanism behind the mediation of irinotecan GI toxicity by gut bacterial enzyme?

A

the inhibition of gut bacterial beta-glucuronidase activity (via antibiotics) decreases diarrhea from irinotecan therapy

38
Q

Choose two main (most common) drug metabolism reactions occurring in the liver.

A
  1. oxidation

2. conjugation

39
Q

True/false: Among P450 enzymes, CYP3A4 is responsible for metabolizing the largest fraction of drugs.

A

true

40
Q

True/false: Portal triad is composed of bile duct, portal vein, and hepatic vein.

A

false → hepatic artery not the hepatic vein

41
Q

True/false: Enzyme inducers of CYP3A4 would likely decrease the systemic exposure of CYP3A4 substrates.

A

true

42
Q

True/false: Enzyme inhibitors of CYP3A4 would likely increase the systemic exposure of CYP3A4 substrates.

A

true

Pharmacokinetics (14 decks)

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