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71 Cards in this Set
- Front
- Back
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Drug clearance I
Cl is characteristic of: |
drug elimination (excretion + metabolism)
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Drug clearance I
Cl is the proportionality constant between: |
the drug amount eliminated per time unit (elimination rate) and the drug concentration in the given compartment
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Drug clearance I
Cl (equation) |
Cl= elimination rate/drug concentration
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Drug clearance II
the equation is model- independent and valid for: |
any time moment and any organ
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Drug clearance II
Cl (equation) rearranged: |
Cl= dose/AUC
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Drug clearance III
Cl is equal to: |
the volume of the fluid completely cleared of the drug per the unit of time
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Drug clearance III
units of Cl: |
mL/min or L/hr
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Drug clearance III
Cl can be defined for: |
compartment and physiologic models
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clearance nomenclature I
for specifications needed: |
elimination organ
process state of drug molecules site of measurement |
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clearance nomenclature I
elimination organ |
liver, kidney, lungs...
(hepatic, renal, pulmonary clearance) |
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clearance nomenclature I
process: |
metabolism, excretion (metabolic or excretory clearance) the description by organ is insufficient because there can be some excretion in liver and some metabolism in kidney
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clearance nomenclature I
state of the drug molecules: |
free, bound, ionized...
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clearance nomenclature I
site of measurement |
plasma, blood
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clearance nomenclature II
an exact description should address all four specifications e.g. |
hepatic metabolic unbound plasma clearance
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clearance nomenclature II
simplifying rules for common types of clearance: |
- the organ specifies the process
(hepatic metabolic--> hepatic) (renal excretory --> renal) - the word 'plasma' omitted - the word 'unbound' omitted |
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clearance nomenclature II
for less common types- |
full name (hepatic excretory blood clearance based on total concentration)
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plasma vs blood clearance
plasma clearance is more frequently reported |
true
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plasma vs blood clearance
blood clearance must be considered when determining the: |
extraction ratio
cl= elimination rate/drug concentration in the given fluid |
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plasma vs blood clearance
for the given elimination process (equation) |
plasma clearance blood conc
------------------------- = -------------------- blood clearance plasma conc |
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clearance: definition for compartment models
the body has apparent Vd with the average drug concentration cp |
true
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clearance: definition for compartment models
the best way to calculate clearance is to use: |
Cl= dose/AUC
because AUC can be easily calculated |
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Clearance: definition for one-compartment model
AUC: |
AUC= D/ke * Vd
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clearance for one-compartment model
Cl= |
ke * Vd
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clearance for multi-compartment models
Cl= |
dose/ sum of a1/b1
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clearance: definition for first order absorption
fast release and plasma/tissue equilibration, first order absoption |
Cl= ke * Vd/F
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total body clearance
clearance characterizes: |
elimination
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total body clearance
processes that contribute to total elimination: |
excretion
metabolism |
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total clearance =
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sum of clearances of individual processes
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the drug amount eliminated by a specific process is proportional to:
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the clearance of that elimination process
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blood flow
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Q = volume/time
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clearance: definition for physiologic models I
(diagram) |
eliminating organ
Q, Ca Q,Cv ---------> ----------> | | eliminated drug Ca= arterial blood Cv=venous |
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clearance: definition for physiologic models II
clearance = |
volume of blood cleared completely of drug per unit time
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clearance: definition for physiologic models II
If the organ eliminates the drug completely (cv=0) then: |
Cl = the blood flow (Q)
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clearance: definition for physiologic models II
If the organ doesn't eliminate the drug completely (cv doesn't = 0) then: |
an adjustment is needed: the blood flow is multiplied by the fraction of drug eliminated
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clearance: definition for physiologic models III
fraction of the drug eliminated= q |
extraction ratio
ER= ca-cv/ca |
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clearance for physiologic models
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Cl= Q * ER
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renal drug excretion
kidney |
-main excretory organ
-two endocrine functions (renin, epo) -cortex and medulla -receives 1/4 of CO, autoregulated flow |
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renal excretion includes:
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--glomerular filtration- structure non-specific
--active tubular secretion- carrier-mediated-->structure specific, energy driven -- tubular reabsorption (active or passive) |
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nephron: function
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see pg 3 slide 6
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glomerular filtration
unidirectional? |
yes
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glomerular filtration
non-specific for small molecules (up to 2000 g/mol), protein-bound drugs are not filtered |
true
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glomerular filtration
driving force: |
the difference in hydrostatic pressure between capillaries and nephrons
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glomerular filtration
measured using drugs that are only filtered: |
inulin(polysaccharide)- xenobiotics
creatinine- physiologic compound |
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active renal secretion
active transport |
-carrier mediated (saturable, competition
- energy dependent |
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active renal secretion
two systems prevailing: |
organic anion transporting peptides(OATPs)
organic cation transporters (OCTs) |
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active renal secretion
extremely rapid for: |
p-amino-hippuric acid (PAHA)- eliminated in single pass
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active renal secretion
endocytosis of peptides: |
also proceeds in proximal tubule, the vesicles are formed from the brush-border membrane and internalized
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tubular reabsorption
active |
vitamines, nutrients, electrolytes
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tubular reabsorption
passive |
water, drugs
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tubular reabsorption
the only way to decrease the drug excretion rate below fu * GFR |
true
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tubular reabsorption
influence of pH in urine: |
non-dissociated molecules have faster reabsorption from renal tubule back into blood than ionized molecules
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tubular reabsorption
influence of urine flow: |
increase in flow decreases the time for reabsorption
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urine formation
renal blood flow (RBF)= |
1/4 CO ~ 1.2L/min
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urine formation
renal plasma flow (RPF) |
RPF= RBF * (1-Hct)
Hct- volume fraction of blood cells ~0.45 |
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glomerular filtration rate is:
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~ 20% of RPF
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urine represents only:
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~1% of filtered volume
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determination of renal clearance I
(equation) |
Clr= excretion rate/plasma concentration
see pg 4 slide 5 and 6 |
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renal excretion I
how much blood passes through the kidney's? |
~ 1.2L/min
(the elementary unit- nephron) |
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renal excretion I
the blood first enters glomeruls where: |
~120 mL/min (GFR) of plasma water with dissolved molecules are filtered into the tubule
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renal excretion I
filtrate passes: |
down the tubule, most of the water and some molecules are reabsored
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renal excretion I
on leaving the glomerulus the blood perfuses the tubule and further transport takes place in: |
- proximal part (secretion, active reabsorption)
- along the whole length (passive reabsorption) |
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renal excretion II
water is also reabsorbed volume reduction to: |
~1%
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renal excretion II
the rates of the first two processes are easily defined, reabsorption is defined as: |
the fast process using the urine/plasma concentration ratio
Clr= Clf + Cls-Clr |
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renal clearance: mechanism
Clr= |
filtration rate + secretion rate- reabsorption rate/ plasma concentration
Clr= Clf + Cls - Clr Clf= Clinulin |
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fraction unbound (in plasma)
(equation) |
fu= 1/1+K*p
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fraction unbound depends on protein binding- the association constant K and concentration p
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true
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glomerular filtration
equation |
Clf = filtration rate/plasma concentration
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clearance of filtration
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Clf = fu * GFR
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for a drug completely unbound in blood, Clf achieves:
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the maximum value, GFR ~ 120 mL/min (inulin, creatinine)
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GFR is also the maximum renal clearance in absense of:
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active secretion and reabsorption
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the drug tightly bound to the blood constituents has low filtration clearance and, if it is not actively secreted, also low renal clearance
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true
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