Exam 1 Bioavailability and Clearance 4 Flashcards
What are the three things within renal excretion?
- filtration → from arterial bloodstream into glomerulus
- secretion → from arterial bloodstream into proximal tubule
- reabsorption → from lumen of nephron into venous bloodstream
Which processes go in the same direction?
filtration and secretion → reabsorption goes in the opposite way
What are the effects of these processes on renal excretion?
filtration and secretion → increases excretion
reabsorption → decreases excretion
What kinds of things get actively reabsorbed?
nutrients
What kinds of things gets passively reabsorbed?
drugs
What is some important info on renal excretion?
- 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)
- 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
- 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)
What is renal clearance (CLr)?
- defined as the proportionality constant relating the rate of urinary excretion and the plasma concentration of drug in the body (Cp)
- CLr = fe*CL
What is some important info to know about filtration?
- occurs in the glomerulus
- depends on MW and unbound drug concentration in plasma (fu)
- small molecules and small proteins are filtered readily and high MW proteins are not filtered well → most small molecule drugs have MW < 1500
- only unbound drug in plasma water is filtered
- SIZE IS LIMITING FACTOR FOR FILTRATION
What is the equation for the rate of drug filtration?
rate of drug filtration = fuCpGFR = Cu*GFR
dAe/dt = CLr*Cp
For a drug that is eliminated ONLY by filtration, what is the equation for renal clearance?
CLr = fu*GFR
What is the relative equations for renal clearance for filtration only, secretion, and reabsorption?
filtration only → CLr = fuGFR
secretion → CLr > fuGFR
reabsorption → CLr < fu*GFR
What is some important information to know about secretion?
- occurs in the proximal tubule
- active carrier mediated process → saturable → there are separate transporters for acids and bases from plasma into urine → neutral drugs are not secreted
- 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)
- 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
- 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
What does secretion depend on?
- plasma protein binding (fu)
2. kidney blood flow
Based on the data, what is the major limiting factor for renal excretion of furosemide?
protein binding → is a low Er drug so the amount of secretion depends on unbound concentration of drug in blood
What is important about penicillins and probenecid?
they both use the same transporters and are organic acids (basically compete for each other’s transporters)
Why does probenecid decrease CLr of amoxicillin?
probenecid and amoxicillin use the same transporters so probenecid decreases renal secretion of amoxicillin and thus decreases the CLr
What is reabsorption?
- occurs along the length of the nephron, associated with reabsorption of water
- 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)
- 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)
What are the factors affecting renal reabsorption of drugs?
- properties of the drug → polarity, ionization
2. physiological factors → urine flow, urine pH
What is the relationship between log P values and hydrophobicity?
large log P value → lipophilic
small log P value → hydrophilic
How does polarity and ionization affect reabsorption?
- polar compounds are not reabsorbed (those with low log P aka hydrophilic)
- ionized compounds are not reabsorbed (those with charges)
How does urine flow affect reabsorption?
- faster urine flow increases drug excretion → greater the free drug concentration gradient, the faster the reabsorption
- high plasma protein binding decreases drug excretion → if more drug is bound, then more will be reabsorbed
What is the equation of renal clearance given with urine flow?
CLr = fu*urine flow (for a drug that is readily reabsorbed)
How does urine pH change?
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
What drugs lead to alkaline urine?
acetazolamide and sodium bicarbonate (but acetazolamide is a diuretic to increase urine flow)
What drugs lead to acid urine?
ammonium chloride and vitamin C → but ammonium chloride is a diuretic to increase urine flow
Why is urine pH important for reabsorption?
important for nonpolar drugs that are weak acids (like salicylates) or weak bases (amphetamine, ephedrine)
- acidification of urine (decreased pH) promotes reabsorption of weak acids and promotes CLr of weak bases
- alkalization of urine (increased pH) promotes reabsorption of weak bases and promotes CLr of weak acids
Name a drug that can increase phenobarbital CLr most significantly?
acetazolamide → want alkaline urine since renal clearance increases with urine and acetazolamide is a diuretic to increase urine flow
Offer a way to enhance drug elimination incase of aspirin overdose.
acetazolamide → want alkaline urine since renal clearance is increased with alkaline urine and acetazolamide is a diuretic to increase urine flow
Offer a way to enhance drug elimination in case of methamphetamine overdose.
ammonium chloride → want acidic urine since excretion is increased with acidic urine and ammonium chloride because it is a diuretic to increase urine flow
In what situations are insensitive to urinary pH?
- drug that is polar in its unionized form is not reabsorbed → gentamycin
- strong acids (pKa < 3) and strong bases (pKa > 12) are completely ionized over urine pH range so they undergo little reabsorption
- 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)
What do we assume when the liver and kidney are the major organs of elimination?
CL = CLh + CLr
What is the one compartment model?
CL = kel*Vd
What do we assume if intestinal metabolism is insignificant for all drugs?
F = Fa*(1-Eh)
What do we assume if drugs are distributed to plasma?
Cb/Cp = 0.5
What is hepatic plasma flow and what is it used to calculate?
0.7 L/min (42 L/hr) and used to calculate hepatic extraction ratio (Eh = CLh/0.7)
What is blood flow to the kidney?
1.2 L/min
What is typical GFR and urine flow?
120 and 1 mL/min respectively
What is filtration limited by?
protein binding and molecular size
What is secretion limited by?
competition over same transporters and protein binding and renal blood flow
What is reabsorption limited by?
urine pH, urine flow, and protein binding
