Exam 1 Bioavailability and Clearance 4

Question 1

What are the three things within renal excretion?

Answer 1

1. filtration → from arterial bloodstream into glomerulus
2. secretion → from arterial bloodstream into proximal tubule
3. reabsorption → from lumen of nephron into venous bloodstream

Question 2

Which processes go in the same direction?

Answer 2

filtration and secretion → reabsorption goes in the opposite way

Question 3

What are the effects of these processes on renal excretion?

Answer 3

filtration and secretion → increases excretion

reabsorption → decreases excretion

Question 4

What kinds of things get actively reabsorbed?

Answer 4

nutrients

Question 5

What kinds of things gets passively reabsorbed?

Answer 5

drugs

Question 6

What is some important info on renal excretion?

Answer 6

1. approximately 20% of cardiac output (1.1 L/min) goes to the kidneys → of this volume, 10% is filtered in the glomerulus which is called the glomerular filtration rate (GFR = 120 mL/min)
2. pores in glomerulus permit the passage of most drug molecules but restrict the passage of blood cells and plasma proteins → only unbound drug is filtered
3. over 90% of the filtered volume is reabsorbed in the renal tubules, with only 1-2 mL/min leaving the kidney as urine → a total of 1.5 L of filtrate is excreted as urine per day (urine flow is 1-2 mL/min)

Question 7

What is renal clearance (CLr)?

Answer 7

1. defined as the proportionality constant relating the rate of urinary excretion and the plasma concentration of drug in the body (Cp)
2. CLr = fe*CL

Question 8

What is some important info to know about filtration?

Answer 8

1. occurs in the glomerulus
2. depends on MW and unbound drug concentration in plasma (fu)
3. small molecules and small proteins are filtered readily and high MW proteins are not filtered well → most small molecule drugs have MW < 1500
4. only unbound drug in plasma water is filtered
5. SIZE IS LIMITING FACTOR FOR FILTRATION

Question 9

What is the equation for the rate of drug filtration?

Answer 9

rate of drug filtration = fuCpGFR = Cu*GFR

dAe/dt = CLr*Cp

Question 10

For a drug that is eliminated ONLY by filtration, what is the equation for renal clearance?

Answer 10

CLr = fu*GFR

Question 11

What is the relative equations for renal clearance for filtration only, secretion, and reabsorption?

Answer 11

filtration only → CLr = fuGFR
secretion → CLr > fuGFR
reabsorption → CLr < fu*GFR

Question 12

What is some important information to know about secretion?

Answer 12

1. occurs in the proximal tubule
2. active carrier mediated process → saturable → there are separate transporters for acids and bases from plasma into urine → neutral drugs are not secreted
3. if rate of excretion > rate of filtration, then can assume secretion has occurred so if CLr > fu*GFR, assume secretion has occurred (reabsorption may have occurred but secretion is greater)
4. high renal excretion drugs (high Er) are good substrates for renal transporters and dissociate rapidly from plasma proteins so as not to limit secretion → amount of secretion is dependent only on renal blood flow → example is para-amino hippurinc acid
5. low renal excretion drugs (low Er) are poor substrates for renal transporters → transportation is the limiting step even though blood sits at the proximal tubule for 30 seconds → amount of secretion depends on unbound concentration of drug in blood and is independent of renal blood flow → example is furosemide

Question 13

What does secretion depend on?

Answer 13

1. plasma protein binding (fu)

2. kidney blood flow

Question 14

Based on the data, what is the major limiting factor for renal excretion of furosemide?

Answer 14

protein binding → is a low Er drug so the amount of secretion depends on unbound concentration of drug in blood

Question 15

What is important about penicillins and probenecid?

Answer 15

they both use the same transporters and are organic acids (basically compete for each other’s transporters)

Question 16

Why does probenecid decrease CLr of amoxicillin?

Answer 16

probenecid and amoxicillin use the same transporters so probenecid decreases renal secretion of amoxicillin and thus decreases the CLr

Question 17

What is reabsorption?

Answer 17

1. occurs along the length of the nephron, associated with reabsorption of water
2. passive process for exogenous products including drugs but active process for many endogenous compounds like vitamins, electrolytes, amino acids, glucose (CLr of glucose is 0)
3. if rate of excretion < rate of filtration, then assume reabsorption has occurred so if CLr < fu*GFR then reabsorption has occurred (secretion may have occurred but reabsorption is greater)

Question 18

What are the factors affecting renal reabsorption of drugs?

Answer 18

1. properties of the drug → polarity, ionization

2. physiological factors → urine flow, urine pH

Question 19

What is the relationship between log P values and hydrophobicity?

Answer 19

large log P value → lipophilic

small log P value → hydrophilic

Question 20

How does polarity and ionization affect reabsorption?

Answer 20

1. polar compounds are not reabsorbed (those with low log P aka hydrophilic)
2. ionized compounds are not reabsorbed (those with charges)

Question 21

How does urine flow affect reabsorption?

Answer 21

1. faster urine flow increases drug excretion → greater the free drug concentration gradient, the faster the reabsorption
2. high plasma protein binding decreases drug excretion → if more drug is bound, then more will be reabsorbed

Question 22

What is the equation of renal clearance given with urine flow?

Answer 22

CLr = fu*urine flow (for a drug that is readily reabsorbed)

Question 23

How does urine pH change?

Answer 23

can vary widely from 4.5 to 7.5 (average 6.3) → variations are due to forced acidification/alkalization, respiratory or metabolic acidosis/alkalosis and drugs

Question 24

What drugs lead to alkaline urine?

Answer 24

acetazolamide and sodium bicarbonate (but acetazolamide is a diuretic to increase urine flow)

Question 25

What drugs lead to acid urine?

Answer 25

ammonium chloride and vitamin C → but ammonium chloride is a diuretic to increase urine flow

Question 26

Why is urine pH important for reabsorption?

Answer 26

important for nonpolar drugs that are weak acids (like salicylates) or weak bases (amphetamine, ephedrine) 1. acidification of urine (decreased pH) promotes reabsorption of weak acids and promotes CLr of weak bases 2. alkalization of urine (increased pH) promotes reabsorption of weak bases and promotes CLr of weak acids

Question 27

Name a drug that can increase phenobarbital CLr most significantly?

Answer 27

acetazolamide → want alkaline urine since renal clearance increases with urine and acetazolamide is a diuretic to increase urine flow

Question 28

Offer a way to enhance drug elimination incase of aspirin overdose.

Answer 28

acetazolamide → want alkaline urine since renal clearance is increased with alkaline urine and acetazolamide is a diuretic to increase urine flow

Question 29

Offer a way to enhance drug elimination in case of methamphetamine overdose.

Answer 29

ammonium chloride → want acidic urine since excretion is increased with acidic urine and ammonium chloride because it is a diuretic to increase urine flow

Question 30

In what situations are insensitive to urinary pH?

Answer 30

1. drug that is polar in its unionized form is not reabsorbed → gentamycin 2. strong acids (pKa < 3) and strong bases (pKa > 12) are completely ionized over urine pH range so they undergo little reabsorption 3. very weak acids (pKa > 8) and very weak bases (pKa < 6) will be unionized in the urinary pH range and will be reabsorbed in this range, resulting in low CLr and insensitive to pH → phenytoin (acid) and propoxyphone (base)

Question 31

What do we assume when the liver and kidney are the major organs of elimination?

Answer 31

CL = CLh + CLr

Question 32

What is the one compartment model?

Answer 32

CL = kel*Vd

Question 33

What do we assume if intestinal metabolism is insignificant for all drugs?

Answer 33

F = Fa*(1-Eh)

Question 34

What do we assume if drugs are distributed to plasma?

Answer 34

Cb/Cp = 0.5

Question 35

What is hepatic plasma flow and what is it used to calculate?

Answer 35

0.7 L/min (42 L/hr) and used to calculate hepatic extraction ratio (Eh = CLh/0.7)

Question 36

What is blood flow to the kidney?

Answer 36

1.2 L/min

Question 37

What is typical GFR and urine flow?

Answer 37

120 and 1 mL/min respectively

Question 38

What is filtration limited by?

Answer 38

protein binding and molecular size

Question 39

What is secretion limited by?

Answer 39

competition over same transporters and protein binding and renal blood flow

Question 40

What is reabsorption limited by?

Answer 40

urine pH, urine flow, and protein binding