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PHRM 501 > Exam 3: Hepatic Clearance > Flashcards

Exam 3: Hepatic Clearance Flashcards

1
Q

The greater the blood flow->

A

the greater the distribution

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2
Q

If the blood flow is the same

A

the greater the partitioning into the tissues

- the slower the distribution

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3
Q

If the partitioning is the same,

A

the larger the organ and the slow the distribution

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4
Q

The net movement of fluid is

A

into the tissues at the arterial end of a capillary and returned to the capillary at the venous end

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5
Q

What can vary with disease state

A

Blood flow and permeabiilty of capillary membranes

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6
Q

The primary metabolic organ is

A

the liver
- 1storgan encountered
•Relatively large organ
•High concentration of metabolic enzymes•High rate of blood flow (~1.5 L/min., ~90 L/hr

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7
Q

The liver

A

is an adaptive organ

- Can accommodate higher concentrations of drugs

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8
Q

Inactivation

A

Drug → inactive metabolite

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9
Q

Activation

A

Pro-drug → drug
• codeine, inactive → morphine, active
• Drug → toxic metabolite
• Meperidine → normeperidine

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10
Q

Quid quo pro

A

Drug → metabolite with similar activity

- Allegra ( fexofenadine)

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11
Q

Phase 1 Metabolism

A
  • Oxidation
  • Reduction
  • Hydrolysis
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12
Q

Phase II Metabolism

A

• Conjugation
- something is added to the molecule
• Glucuronide
• Sulfate

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13
Q

Metabolism generally makes molecules

A

hydrophilic molecules that are more readily excreted

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14
Q

Which renal process would be most affected

by how hydrophilic a molecule is?

A

Reabsorption

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15
Q

Phase I Enzymes

A

• Cytochome P450 enzymes
(CYP450s)
• Flavin-containing monooxygenases
(FMOs)

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16
Q

Examples of Phase I Metabolism

A

• Oxidation
- N-dealkylation

• Hydrolysis
- Aromatic hydroxylation

• Reduction
- Nitro to amine

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17
Q

Examples of Phase II Metabolism

A
  • Acetylation
  • Glucuronidation
  • Glutathionylation
  • Methylation
  • Sulfation
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18
Q

Metabolism Generalities

A
  • Phase I can occur without Phase II and vice versa

* Phase I can occur after Phase II and vice versa

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19
Q

Portal triad

A
  • Hepatic artery (Inlet: ~20% flow)
  • Portal vein (Inlet: ~80% flow)
  • Common bile duct (Outlet)
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20
Q

Primary function of Hepatic

A

Serves as a
filter between blood from GI
tract and systemic circulation

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21
Q

• Primary cell type of lIver

A

Hepatocytes

• Local blood source: sinusoids

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22
Q

Influx

A

Sink effect for diffusion into hepatocyte

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23
Q

More metabolism

A

loss of drug (typically)

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24
Q

Efflux

A

Pump drug out

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25
Q

Other characteristics of Efflux

A

Return drug to circulation for potential therapeutic action
• Send drug to bile for potential removal from body
• Send drug to bile for potential reabsorption from intestine

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26
Q

Enterohepatic Cycling

A

• Circulation between liver and intestine via gall bladder
•>90% of bile acids are reabsorbed in the gut and taken back into hepatocytes
-Often glucuronide metabolites

A drug enters the liver via the portal vein and then is returned to the small intestine in the bile via the gall bladder

  • or its reabsorbed into portal circulation
  • Distributed to systemic circulation via the central vein
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27
Q

Cytochrome P450s

A
  • aka CYP450, CYPs
  • Major enzyme superfamily
  • Use oxygen and NADPH to carry out reactions
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28
Q

Flavin-containing monooxygenases

A
  • Aka FMOs
  • Major enzyme superfamily
  • Comparatively minor contributors to metabolism
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29
Q

Cytochrome P450s are responsible for:

A
  • metabolism of dietary and xenobiotics
  • Synthesis of steroids and signaling molecules
  • Production of bile acids
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30
Q

Cytochrome P450s are primarily found

A

in the smooth endoplasmic reticulum of hepatocytes

- But, some also in the GI tract, kidney, lungs and CNS (albeit much less)

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31
Q

CYP Nomenclature

A

More than 50 different CYPs in people

- Grouped based on amino acid sequence similarity

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32
Q

Genetic family:

A

CYP1
• CYP2
• CYP3

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33
Q

Genetic sub-family:

A
  • CYP2A
  • CYP2B
  • CYP2C
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34
Q

Gene number:

A
  • CYP2C8
  • CYP2C9
  • CYP2C19
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35
Q

CYP Specificity

A
  • Some CYPs are very specific
  • CYPs have relatively broad specificity
  • One CYP can act on many drugs
  • And a drug may be metabolized by more than one CYP
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36
Q

Activity and Distribution of Phase I Enzymes

A

The enzymes present in the largest quantities don’t necessarily equate to those contributing the
greatest activity

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37
Q

CYP 3A4 is responsible for

A

> 50% of the metabolism of therapeutic drugs

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38
Q

Phase II Enzymes are mainly

A

‘transferases’

- Variable location (cytosolic, mitochondrial, membrane-bound)

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39
Q

Transferases

A
  • Transfer a functional group/molecule to another

• Conjugate an endogenous molecule onto xenobiotic

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40
Q

Activity and Distribution of Phase II Enzymes

A

Phase II enzymes normally terminate biological
activity
- One exception to this is morphine which when
glucuronidated becomes more active!

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41
Q

Glucuronidation and sulfation cause log P to

A

decrease

42
Q

UGTs: Glucuronyltransferases

A

40%-70% of therapeutic drugs become glucuronidated

43
Q

Metabolism usually reduces

A

biological activity
• Sometimes it can be used to increase biological activity
beneficially
• But sometimes it can form toxic entities

44
Q

Enzymes exhibit

A

Michaelis-Menten kinetics

45
Q

Under sub-saturation conditions, the rate of

conversion is

A

proportional to [drug]

46
Q

Once saturated with substrate

A

an enzyme has a maximum rate (Vmax)

47
Q

The [substrate] at which v=½Vmax

A

is the Km

Michaelis-Menten constant

48
Q

For first order elimination, as the plasma

concentration of drug increases

A

the rate of elimination increases

49
Q

For zero order elimination, the enzymes are

working as fast as they can

A

so the rate of elimination is maximal and at a plateau!

50
Q

If the plasma drug concentration was high

enough,

A

all drugs would reach the zero-order range

51
Q

Most drugs have a therapeutic range

within

A

the linear portion of the Michaelis-Menten plot

52
Q

The rate of conversion (v) increases with

A

[Drug]

53
Q

V =

A

Vmax * [C] / Km + [C]

54
Q

If we have an overdose, we run the risk of saturating the capacity of enzymes to
metabolize the drug and it can build up

A

Since a drug may be metabolized by more than
one pathway, other pathways may take over
- Some of those pathways may yield toxic
metabolites!
- If we overwhelm ‘good’ pathways, ‘bad’
pathways may prevail!

55
Q

Extraction Ratio (E)

A

Efficacy of an organ to remove a drug from the bloodstream

- Includes both metabolism and excretion

56
Q

Extraction Ratio (E) is expressed as

A

a fraction from 0-1
O being no removal of drug
1 being complete removal of drug

57
Q

Eh=

A

([C]in-[C]out)/[C]in

58
Q

Clearance by an organ is a function of the

A

extraction ratio (E) and blood flow (Q) to a given organ

59
Q

Clearance can be

A
  • flow-limited
  • capacity limited
    • The organ simply isn’t very efficient at removing the drug
60
Q

More blood flow means

A

more clearance

61
Q

Clearance is also dependent

A

on the degree of protein-binding
• Only free drug is available to be metabolized or excreted
• The levels of proteins in the blood vary with disease state

62
Q

Flow-limited:

A

if the fraction of drug unbound and metabolic activity of the liver is highE≈1), then clearance is limited by blood flow

63
Q

Capacity limited:

A

if the blood flow is high, but the fraction of drug unbound and metabolic
activity of the liver is low (E≈0), then clearance is limited by the capacity of the liver to
remove the drug

64
Q

What determines the Extraction Ratio?

A
  • Blood flow to the organ (Q)
  • How much drug is in the unbound form (fu)
  • ## “Intrinsic clearance” (Clint)
65
Q

“Intrinsic clearance” (Clint)

A

is the enzyme-mediated clearance that would result when in the absence of physiological limitations

66
Q

When to use Therapeutic Drug Monitoring

A 
Wide interpatient variability
• Varied absorption
• Varied distribution
• Varied metabolism
• Disease states
• Drug-drug/drug-nutrient interactions
67
Q

Polymorphisms are

A

Genetic mutations that cause increased/decreased/loss of activity/presence
- Changes in copy number
• Changes in rate of substrate conversion (Vmax)
• Changes in substrate affinity (Km)

68
Q

Polymorphisms range from

A 
no activity to ultrarapid conversion!
• Poor metabolizers (PM)
• Intermediate metabolizers (IM)
• Extensive metabolizers (EM)
• Ultrametabolizers (UM
69
Q

CYP2D6

A

74 known alleles
• Range from no activity to ultrarapid conversion!
• 7-10% of Caucasians are poor metabolizers
• Perhexiline withdrawn from market in 1988 due to toxic effects on PMs

70
Q

If an individual is a poor metabolizer (PM), would you expect clearance to be higher or lower than average?
A. Higher
B. Lower

A

B. Lower

71
Q

drugs can interact in a variety of ways

A
  • Compete for transporters
  • Compete as a substrate for metabolic enzymes
  • Inhibit metabolic enzymes
  • Induce enzyme expression
72
Q

If clearance reduced, drug concentration may

A

reach toxic levels

73
Q

If clearance increased,

A

drug concentration may not reach therapeutic levels

74
Q

Enzyme Induction

A

Increased number of drug-metabolizing enzymes in response to a drug or environmental constituent
- Enzyme synthesis initiated within 24 hours
of exposure
• Increases over 3-5 days
• Decreases over 1-3 weeks after inducing
agent is discontinued

75
Q

Increased nuclear receptor (NR)-mediated gene transcription

A

Receptors bind to steroid and thyroid hormones in the cytoplasm and then migrate to the nucleus. Signaling
is very complex and leads to both activation and repression activities.
• Response time: Slow, 30 min. to hours

76
Q

If we have more an enzyme that acts on a drug, how is k likely affected?

A

K will increase

77
Q

If we have more an enzyme that acts on a drug, how is t1/2 likely affected?

A

t 1/2 will decrease

78
Q

If we have more an enzyme that acts on a drug, how is E likely affected?

A

E will increase

  • if enzyme goes up we have more ability to extract the drug from circulation
  • If E goes up, Cl goes up
79
Q

If we have more an enzyme that acts on a drug, how is Cl likely affected?

A

Cl increases

80
Q

If we have more an enzyme that acts on a drug, how is F likely affected?

A

F will decrease

81
Q

What is the relationship between K and t1/2

A

Inverse relationship

as K goes up t 1/2 goes down and vice versa.

82
Q

Enzyme Induction

A

CYP3A, CYP2A-CYP2E are inducible

83
Q

CYP3A4 inducing agents include

A
  • Phenytoin
  • Glucocorticoids
  • St. John’s Wort
84
Q

CYP2D6 inducing agents are

A
  • Dexamethasone

* Rifampin

85
Q

Enzymes aren’t the only inducible biomolecules

P-glycoprotein is

A

P-glycoprotein is inducible

86
Q

what is P-glycoprotein

A

p-GP is an efflux transporter that removes drugs from cells

• Carbamazepine

87
Q

P450s

A

found on CYP3A4 in intestinal wall
• Induced by St. John’s Wort, phenytoin, glucocorticoids
• Inhibited by grapefruit juice, omeprazole, ketoconazole

88
Q

p-GP

A

This is on the Apical membrane of our enterocytes
- a efflux transporter
• Induced by St. John’s Wort, phenytoin, rifampin
• Inhibited by erythromycin, ketoconazole

89
Q

What happens to a drug that is a CYP3A4 substrate if CYP 3A4 is induced?

A

Plasma Drug conc. will be lower

If we have a substrate and we add more, then we will see more breakdown of that drug

90
Q

What happens to a drug that is a CYP3A4 substrate if CYP 3A4 is inhibited?

A

The Plasma Drug Conc. will increase

91
Q

What happens to a drug that is a p-GP substrate if p-GP is induced?

A

The Plasma conc. is going to go down

92
Q

What happens to a drug that is a p-GP substrate if p-GP is inhibited?

A

The plasma conc. is going to go up

93
Q

Why cant you take this with grapefruit juice

A

CYP3A4 can be inhibited by grapefruit juice

94
Q

CYP3A4 is an

A

enzyme that metabolizes and breaks the drug down

95
Q

The apical membrane faces what?

A

the lumen

96
Q

If someone is taking St. Johns Wart, they are

A

increasing their metabolic ability for the drug

  • also increasing ability of the drug to get out of the cells
  • ultimately their plasma drug conc. is going to be double
  • conc. will be much lower bc not only is it being more metabolically acted on but its also having the ability to be shunted out much easier.
97
Q

Some drugs induce their own metabolism

A

Carbamazepine is a drug that is metabolized primarily by 3A4
• It also is an inducer of CYP 3A4, 1A2, and 2C9
• Thus, it induces its own metabolism!

98
Q

Some drugs induce their own efflux

A

Carbamazepine is also an inducer of p-GP

• Thus, it induces its own removal!

99
Q

If we know that a drug induces its own metabolism, how will the following PK parameters be affected:

A
  • F will go down
  • t1/2 will go down
  • Cl will will go up
  • Ke will go up
100
Q

Wide substrate selectivity + many inhibitors

A

significant potential for

drug interactions

PHRM 501 (21 decks)

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