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z Biopharm > Elimination > Flashcards

Elimination Flashcards

1
Q

Match the following terms regarding elimination:

  1. Liver
  2. Kidney
  3. Bile - feces

A. major source of elimination. glomerular filtration, tubular secretion + reabsorption. goes into urine. HYDROPHILIC molecules.
B. usually a minor source of elimination. eliminates (larger) LIPOPHILIC xenobiotics and metabolites.
C. major source of elimination. metabolizes xenobiotics and helps with transport of more polar metabolites into bloodstream.

A

Liver - major source of elimination. metabolizes xenobiotics and helps with transport of more polar metabolites into bloodstream.

Kidney - major source of elimination. glomerular filtration, tubular secretion + reabsorption. goes into urine. HYDROPHILIC molecules.

Bile: feces - usually a minor source of elimination. eliminates (larger) LIPOPHILIC xenobiotics and metabolites.

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2
Q

While a kidney has a _______ type of capillary, that is highly permeable to water, liver has a _________ type of capillary with larger junctions and discontinuities.

A

Fenestrated; Discontinuous

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3
Q

(T/F) Metabolites have a tougher time getting into tissues and they can be easily removed through different routes of elimination.

A

True!

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4
Q

Match the following terms to their definition regarding transport proteins:

  1. Channels
  2. Carriers
  3. Influx proteins
  4. Efflux proteins

A. bring molecules out of the cell
B. facilitated primary and secondary active transport (saturable)
C. diffusion (can be gated/regulated)
D. bring molecules into cell

A

Channels - diffusion (can be gated/regulated)
Carriers - facilitated primary and secondary active transport (saturable)
Influx proteins - bring molecules into cell
Efflux proteins - bring molecules out of the cell

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5
Q

For the intestine, the basal side is towards the _______ and apical side is towards the ________. For the BBB, basal side is towards ________ and apical side is towards _______.

A

Blood; lumen

Brain; blood

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6
Q

What are the three major families that account for more than 50% of xenobiotic transport across membrane?

A
  1. ATP-binding cassette superfamily (ABC)
  2. Solute carrier superfamily (SLC)
  3. Major facilitator superfamily (MFS)
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7
Q

Match the major families involved in Phase 0 and Phase III of metabolism to what they transport:

  1. ATP-binding cassette superfamily (ABC)
  2. Solute carrier superfamily (SLC)
  3. Major facilitator superfamily (MFS)

A. transports SMALL SOLUTE MOLECULES of biological importance
B. transports SMALL, INTERMEDIATE and MACROMOLECULES. INFLUX and EFFLUX
C. transports ANIONS, CATIONS, PEPTIDES, and ENDOGENOUS molecules

A

ATP-binding cassette superfamily (ABC) - transports SMALL, INTERMEDIATE and MACROMOLECULES. INFLUX and EFFLUX

Solute carrier superfamily (SLC) - transports ANIONS, CATIONS, PEPTIDES, and ENDOGENOUS molecules

Major facilitator superfamily (MFS) - transports SMALL SOLUTE MOLECULES of biological importance

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8
Q

How are CYP enzymes and Multiple Resistance Proteins involved in antibiotic resistance?

A

Multiple resistance proteins are pumps that remove the antibiotics from the microbe cell so the microbe doesn’t die.

CYP enzymes in microbes can have mutations to have a higher affinity for the antibiotic (higher metabolism rate) so they can eliminate/disactivate it quickly.

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9
Q

What are the two steps to renal elimination?

A
  1. Glomerular filtration
  2. Tubular secretion and reabsorption
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10
Q

What happens in glomerular filtration?

A

Blood enters the Bowman’s capsule with highly FENESTRATED blood vessels. Anything that fit through the fenestrated pores escapes blood stream, following its CONCENTRATION GRADIENT, then passes into proximal tubule.

It is usually SMALL WATER MOLECULES, HYDROPHILIC MOLECULES that are filtered out of the blood in glomerular filtration.

Lipophilic molecules can diffuse out of plasma into the capsule following their concentration gradient.

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11
Q

What happens in tubular secretion and elimination? Make sure to talk about the regions of loop of Henle.

A

The molecules (water n more) that make out of the plasma during glomerular filtration are passed down to the LOOP OF HENLE, which REGULATES WATER and SOLUTES.

In the DESCENDING loop of henle, the water is removed, increasing the concentration of solutes (ions) in the urine. In the ASCENDING loop, the ions are reabsorbed into the blood following their concentration gradient.

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12
Q

How can the ascending loop of Henle act as a secondary elimination of drugs and also anti-elimination of drugs?

A

Secondary elimination: if the drug (lipophilic xenobiotic) concentration is higher in the blood than in the urine, more of the drug from the blood can move into the urine through passive transport to be excreted out.

Anti-elimination: if the drug (lipophilic xenobiotic) concentration is higher in the urine than in the blood, the drug can be be removed through passive transport and make its way back to blood + circulation.

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13
Q

Descending limb is highly permeable to ______ but impermeable to ________. While the ascending limb is highly permeable to ________ but nearly impermeable to _______.

A

Water; Solutes

Solutes; Water

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14
Q

What is tubular reabsorption?

A

The molecules on their way out to be excreted as urine get reabsorbed in the blood in the loop of Henle.

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15
Q

What four pathways can the molecules take to be reabsorbed back into the blood from urine?

A
  1. Paracellular path
  2. Transcellular path
  3. Active transport
  4. Passive transport
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16
Q

What is the pH effect on urinary excretion of acidic molecules?

A

Lower pH: more HA/neutral form –> easily reabsorbed into blood

High pH: more charged form –> stays in urine and gets excreted

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17
Q

What is the pH effect on urinary excretion of basic molecules?

A

Lower pH: more charged form –> stays in urine and gets excreted

High pH: more neutral form –> easily reabsorbed into blood

18
Q

(T/F) The kinetics of xenobiotic elimination is the same as the kinetics of xenobiotic absorption, distribution and metabolism.

A

True! Obeys Michaelis-Menten kinetics. Most are removed through urine following 1st order kinetics. When xenobiotic concentrations saturate metabolic and clearance mechanisms, they follow zero order kinetics.

19
Q

(T/F) The higher the drug concentration in the plasm, the greater the amount metabolized and eliminated.

A

True!

20
Q

(T/F) In first order kinetics, it takes 5 half lives for >90% of xenobiotic to be eliminated and 10 half lives for >99% to be eliminated.

A

True!

21
Q

(T/F) In zero order kinetics, it takes 2 half lives for >90% of xenobiotic to be eliminated and 4 half lives for >99% to be eliminated.

A

False! Zero order kinetics doesn’t have any half lives. There is a constant amount of the xenobiotic being eliminated per unit time.

22
Q

What is CLEARANCE? What are the two factors it depends on?

A
  • volume of body fluid from which a substance is IRREVERSIBLE REMOVED per unit time.
  • CONSTANT
  • does not depend on route of administration

Two factors:
1) Rate of elimination
2) Drug concentration

23
Q

What is the EXTRACTION RATIO? What does it quantify?

A

Extraction ratio is the rate of XENOBIOTIC REMOVAL from the PLASMA by an organ of elimination, divided by RATE at which the XENOBIOTIC is PRESENTED to the organ. (clearance/flow rate)

It quantifies the efficiency or removal.

24
Q

An extraction ratio close to 0 indicates:

A

most drug escapes elimination during a single pass through the organ

25
Q

An extraction ratio close to 1 indicates:

A

most drug is eliminated during a single pass through the organ

26
Q

What are the four properties of both substance and organism that clearance may be influenced by?

A
  1. Organ blood flow
  2. Protein binding (if it’s bound, it’s not filtered/eliminated)
  3. Intrinsic ability of the organ to eliminate the drug (like the size of fenestrations, etc)
  4. Flow of fluid excretion (sweating or not)
27
Q

What are the four different mechanisms for clearance?

A
  1. Hepatic (metabolism)
  2. Renal (unchanged through urine)
  3. Lung (unchanged through expiration)
  4. Bile –> Feces
28
Q

(T/F) A decrease in hepatic or renal clearance prolongs half life of a drug (the amount of time it takes your body to reduce drug by half).

A

True! This favours bioavailability.

29
Q

Match the following terms regarding renal clearance of xenobiotics for the average person:

  1. Xenobiotics with clearance of 100-150mL/min
  2. Xenobiotics with clearance less than 100 mL/min
  3. Xenobiotics with clearance greater than 150 mL/min

A. Actively secreted
B. Filtered at the glomerulus
C. Reabsorbed in the blood

A

Xenobiotics with clearance of 100-150mL/min - filtered at the glomerulus

Xenobiotics with clearance less than 100 mL/min - reabsorbed

Xenobiotics with clearance greater than 150 mL/min - actively secreted

CLrenal = (urine flow*urine concentration) / plasma concentration

30
Q

What is the relationship between elimination half-life and volume of distribution?

A

As volume of distribution gets bigger, it takes longer to clear half of the xenobiotic (half-life increases).

31
Q

What is biliary excretion?

A

A route of elimination; probably the second most important route after renal.

The drug is removed from the HEPATOCYTE and then dumped/diffused out of blood and pumped into the BILE which is secreted into the INTESTINE.

32
Q

Drugs with a molecular weight greater than 500 daltons are most excreted in _______, while drugs with a molecular weight less than 300 daltons are excreted in _______.

A

Bile; Urine

*big drugs can’t escape through the fenestrations in the capillaries of kidneys to be in urine.
*in between, they are excreted in both

33
Q

How can the conjugated xenobiotic in our intestine (ready to be excreted in feces) be absorbed in the blood? What is this process?

*conjugated in the liver through Phase II metabolism then made its way to the intestine through bile

A

Microbes in our intestine can deconjugate the conjugate.

For example, there can be enzymatic breakdown of glucuronide to use for energy.

ENTERO-HEPATIC RECYCLING

34
Q

What is pulmonary excretion?

A

LIPOPHILIC MOLECULES (xenobiotics) eliminated by lungs through expired air.

*intact gaseous drugs excreted but not usually their metabolites (which are polar).

35
Q

What is salivary excretion?

A

Elimination of substances through passive diffusion and active transport through the saliva.

*Unionized lipid soluble molecules excreted passively

36
Q

What kind of taste in mouth indicates of salivary elimination?

A

Bitter after-taste

37
Q

Match the following excretory routes to their mechanisms + drugs excreted:

  1. Urine
  2. Bile
  3. Lung
  4. Saliva
  5. Milk
  6. Sweat

A. Passive diffusion. (Gaseous & volatile, blood + tissue insoluble drugs)
B. Passive diffusion. (Free, unionized lipophilic drugs)
C. Glomerular filtration, Active tubular secretion, Active tubular reabsorption and Passive tubular reabsorption. (Free, hydrophilic, unchanged drugs/metabolites of MW < 300)
D. Passive diffusion & Active transport. (Free, unionized, lipophilic drugs, some polar drugs)
E. Active secretion (of drugs from hepatocytes into biliary secretion). (Hydrophilic, unchanged drugs/metabolites/conjugates of MW > 500)
F. Passive diffusion. (Free, unionized, lipophilic drugs)

A

Urine - Glomerular filtration, Active tubular secretion, Active tubular reabsorption and Passive tubular reabsorption. (Free, hydrophilic, unchanged drugs/metabolites of MW < 300)

Bile - Active secretion (of drugs from hepatocytes into biliary secretion). (Hydrophilic, unchanged drugs/metabolites/conjugates of MW > 500)

Lung - Passive diffusion. (Gaseous & volatile, blood + tissue insoluble drugs)

Saliva - Passive diffusion & Active transport. (Free, unionized, lipophilic drugs, some polar drugs)

Milk - Passive diffusion. (Free, unionized, lipophilic drugs)

Sweat - Passive diffusion. (Free, unionized lipophilic drugs)

38
Q

What is the general goal of therapeutic dosing and frequency?

A

Design an optimal schedule such that peak (highest) plasma concentration of drug is BELOW toxic concentration and the trough (lowest) is ABOVE minimally effective level.

*maintain a steady plasma level within the therapeutic window

39
Q

What is Css? With what is it best acheived?

A

Steady state concentration

  1. Continuous IV infusion
  2. Subcutaneous implant
  3. Sustained release oral preparation
40
Q

What three factors determine steady state concentration?

A
  1. Bioavailability (ADM)
  2. Dosing (dosing/time interval)
  3. Clearance (E)
41
Q

(T/F) Once Css is achieved with loading dose, subsequent doses needed only to replace amount being eliminated.

A

True!

42
Q

(T/F) The highest rate of elimination is at the initial exposure while the highest rate of absorption is at Cmax.

A

False! The highest rate of elimination is at the Cmax while the highest rate of absorption is at the initial exposure.

z Biopharm (9 decks)

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