Download Lecture 8 (One compartment IV model for renal clearance

1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered by IV bolus to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
The intent of this slide pack is to evaluate Renal
Clearance of a drug …
How much moxi is in the urine ?
But first, although we have already analyzed
plasma data, as a review calculate volume, AUC,
K, half-life and clearance. Then:
1. How much unchanged moxi is in the urine
at 12 hrs? ..at 36 hrs? Calculate K and ke.
from urine data.
2. What is the ClR of moxifloxacin?
1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered by IV bolus to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
The intent of this slide pack is to evaluate Renal
Clearance of a drug …
How much moxi is in the urine ?
But first, although we have already analyzed
plasma data, as a review calculate volume, AUC,
K, half-life and clearance. Then:
1. How much unchanged moxi is in the urine
at 12 hrs? ..at 36 hrs? Calculate K and ke.
from urine data.
2. What is the ClR of moxifloxacin?
1-Compartment IV Dosing
Analysis of
Concentration –Time Data
This data set provided is identical in
many ways to the tobramycin data set
analysed in Slide Pak 07.
While the solution to volume, AUC,
K, half-life and clearance
is shown briefly in the following slides,
you should complete the calculation of
these parameter values independently
… for practice.
Class time will not be spent
reviewing the method of calculation of
the initial concentration, AUC,
K, half-life or clearance.
1-Compartment IV Dosing
Analysis of Concentration –Time Data
You need to calculate the initial concentration,
AUC, K, half-life and clearance.
You must FIRST determine the log of the concentration
and then from any pair of points (or using all data in Excel)
determine the slope. K is be determined from inspection of the data,
graphical methods or by calculation of the slope.
1-Compartment IV Dosing
Analysis of Concentration –Time Data
Estimation of K. K is the slope of the line (t=2 to 12 hr)
K
= -2.303[log(C2) – log(C1)] / (t2 - t1)
= -2.303[log(1.16) – log(2.32)] / (12 – 2)
= -2.303[0.064 – 0.365] / (10)
= -2.303[ - 0.301]/10
= 0.0693hr-1 T½ = 10.0 hr. Excel = 0.694 hr-1
1-Compartment IV Dosing
K
0.0694 hr-1
Volume
150.12 L
Analysis of Concentration –Time Data
Using K, we can then estimate the initial concentration by
extrapolation. Then calculate the volume & AUC by trapezoidal rule
between each time point (or the pharmacokinetic method).
A variety of estimates of K are possible given the concentrations.
The Excel sheet (posted) provides a range of answers.
Those calculated by hand should be very similar.
1-Compart.IV Dosing
Volume
150.12 L
AUC
38.38 mg*hr/L
K
0.0694 hr-1
T½
9.98 hr
Cl
10.42L/hr
1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered by IV bolus to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were
drawn following the dose and the plasma concentration determined.
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Parameter Estimates
K = 0.0694 hr-1
T½ = 9.98 hr
AUCI =38.38 mg*hr/L
V = 150.12 L
Graph Patient Data
What model best
describes this profile?
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
16 20
Hours
24
28
32
36
Terminal elimination
phase is log-linear…
1 Compartment
Model
with first order
elimination (K)
Graph Patient Data
What model best
describes this profile?
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
16 20
Hours
24
28
32
36
Graph Patient Data
What model best
describes this profile?
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
16 20
Hours
24
28
32
36
kH = kM1 + kM2
KNR = 20% excreted into
bile as unchanged drug.
Graph Patient Data
What model best
describes this profile?
It is known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged. A further 20% is excreted unchanged in the bile
and the rest is metabolised to either M1 (sulpho) or M2 (acyl-glucuronide)
Concentration (mg/L)
10.0
1.0
0.1
0
4
8
12
16 20
Hours
24
28
32
36
K = ke + kH + kNR
1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered by IV bolus to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged.
The intent of this slide pack is to evaluate Renal
Clearance of a drug …
How much moxi is in the urine ?
But first, although we have already analyzed
plasma data, as a review calculate volume, AUC,
K, half-life and clearance. Then:
1. How much unchanged moxi is in the urine
at 12 hrs? ..at 36 hrs? Calculate K and ke.
from urine data.
2. What is the ClR of moxifloxacin?
1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered by IV bolus to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged.
Urine collection following the 400-mg IV dose yields:
Time
(hr)
0
2
6
12
24
36
Plasma Urine
Conc Collection
(mg/L) Period
(hr)
no sample
2.32
1.76
1.16
0.50
0.22
0– 4
4- 8
8 - 16
16 - 32
32 - 40
Amount
Urine Urine Recovered
Volume conc
in Urine
(mL) (mg/L)
(mg)
290
295
490
1060
555
0.060
0.045
0.036
0.015
0.006
17.40
13.28
17.64
15.90
3.330
Urinary
Excretion
Rate
(mg/hr)
1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered by IV bolus to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged.
Calculate the Urinary excretion Rate (mg/hr):
Amount recovered in urine / duration of urine collection.
Time
(hr)
0
2
6
12
24
36
Plasma Urine
Conc Collection
(mg/L) Period
(hr)
no sample
2.32
1.76
1.16
0.50
0.22
0– 4
4- 8
8 - 16
16 - 32
32 - 40
Amount
Urine Urine Recovered
Volume conc
in Urine
(mL) (mg/L)
(mg)
290
295
490
1060
555
0.060
0.045
0.036
0.015
0.006
17.40
13.28
17.64
15.90
3.330
Urinary
Excretion
Rate
(mg/hr)
17.40 mg / 4 hr
1-C: Renal and Hepatic Elimination
400 mg of moxifloxacin is administered by IV bolus to Mr BB, a
68 yr old male who weighs 75 kg. Blood samples were drawn
following the dose and the plasma concentration determined. It is
known that about 20% of a moxifloxacin dose is excreted in the
urine unchanged.
Calculate the Urinary excretion Rate (mg/hr):
Amount recovered in urine / duration of urine collection.
Time
(hr)
0
2
6
12
24
36
Plasma Urine
Conc Collection
(mg/L) Period
(hr)
no sample
2.32
1.76
1.16
0.50
0.22
0– 4
4- 8
8 - 16
16 - 32
32 - 40
Amount
Urine Urine Recovered
Volume conc
in Urine
(mL) (mg/L)
(mg)
290
295
490
1060
555
0.060
0.045
0.036
0.015
0.006
17.40
13.28
17.64
15.90
3.330
Urinary
Excretion
Rate
(mg/hr)
4.350
3.319
2.205
0.994
0.416
Renal Clearance of moxifloxacin
When evaluating Aminoglycoside Renal Clearance
(following IV dose with no metabolism and complete renal excretion)
we observed:
ClR = ClT
and therefore, ClNR = 0 L/hr
It would have also been apparent that
the amount excreted in the urine after infinite time (Ae0-)
would equal the dose.
… that an Excretion Rate vs. Time plot
had a slope proportional to K
…that an Excretion rate vs. mid point plasma concentration
had a slope equal to Renal clearance (ClR).
But now, moxi has other routes of elimination…?
Renal Clearance of moxifloxacin
When evaluating Aminoglycoside Renal Clearance
(following IV dose with no metabolism and complete renal excretion)
we observed:
ClR = ClT
and therefore, ClNR = 0 L/hr
Calculations to complete
It would have also
beenExcretion
apparent rate
that vs. Time.
1. Plot
the amount excreted in the
after infinite
time (Ae0-)
2. urine
Calculate
K
would equal
theExcretion
dose.
3. Plot
rate vs.
mid-point plasma conc.
… that an Excretion
Rate vs. Time
4. Calculate
Renalplot
clearance
had a slope5.proportional
to K
Calculate ke
6. Determine Ae0-
…that an Excretion rate vs.
point plasma
concentration
7. mid
Establish
some principles
had a slope equal to Renal
clearance (ClR).
of Elimination
But now, moxi has other routes of elimination…?
1-C: Renal and Hepatic Elimination
Plot Excretion Rate vs. Time.
Plot at the mid point of the collection period
as this is the time which most accurately reflects the rate
Time
(hr)
0
2
6
12
24
36
Plasma Urine
Conc Collection
(mg/L) Period
(hr)
no sample
2.32
1.76
1.16
0.50
0.22
0– 4
4- 8
8 - 16
16 - 32
32 - 40
Amount
Urine Urine Recovered
Volume conc
in Urine
(mL) (mg/L)
(mg)
290
295
490
1060
555
0.060
0.045
0.036
0.015
0.006
17.40
13.28
17.64
15.90
3.330
Urinary
Excretion
Rate
(mg/hr)
4.350
3.319
2.205
0.994
0.416
1-C: Renal and Hepatic Elimination
Plot Excretion Rate vs. Time
Slope = -K/2.303
1-C: Renal and Hepatic Elimination
Plot Excretion Rate vs. Time
Urine Data
Slope = -K/2.303
= - 0.030
K
= -0.030 * -2.303
= 0.0687 hr-1
T½ = 10.084 hr
1-C: Renal and Hepatic Elimination
Plot Excretion Rate vs. Time
Change in the Rate at which
drug appears in the urine
( Ex. Rate) is proportional
to concentration in serum
and slope is –K/2.303.
Renal Clearance of moxifloxacin
When evaluating Aminoglycoside Renal Clearance
(following IV dose with no metabolism and complete renal excretion)
we observed:
ClR = ClT
and therefore, ClNR = 0 L/hr
Calculations to complete
It would have also
beenExcretion
apparent rate
that vs. Time.
1. Plot
the amount excreted in the
after infinite
time (Ae0-)
2. urine
Calculate
K
would equal
theExcretion
dose.
3. Plot
rate vs.
mid-point plasma conc.
… that an Excretion
Rate vs. Time
4. Calculate
Renalplot
clearance
had a slope5.proportional
to K
Calculate ke
6. Determine Ae0-
…that an Excretion rate vs.
point plasma
concentration
7. mid
Establish
some principles
had a slope equal to Renal
clearance (ClR).
of Elimination
But now, moxi has other routes of elimination…?
1-C: Renal and Hepatic Elimination
Plot Excretion Rate vs. Mid-point Plasma concentration.
Plot the excretion rate vs. the
concentration at the mid point of the collection period
Time
(hr)
0
2
6
12
24
36
Plasma Urine
Conc Collection
(mg/L) Period
(hr)
no sample
2.32
1.76
1.16
0.50
0.22
0– 4
4- 8
8 - 16
16 - 32
32 - 40
Amount
Urine Urine Recovered
Volume conc
in Urine
(mL) (mg/L)
(mg)
290
295
490
1060
555
0.060
0.045
0.036
0.015
0.006
17.40
13.28
17.64
15.90
3.330
Urinary
Excretion
Rate
(mg/hr)
4.350
3.319
2.205
0.994
0.416
1-C: Renal and Hepatic Elimination
Plot Excretion Rate vs. Mid-point Plasma concentration.
Slope = ClR (L/hr)
1-C: Renal and Hepatic Elimination
Renal Clearance & Urinary Excretion
Slope = ClR (L/hr)
= 1.864 L/hr
1-C: Renal and Hepatic Elimination
Renal Clearance & Urinary Excretion.
Slope = ClR (L/hr)
CLR = 1.864 L/hr
Plasma Data;
ClT = 10.42 L/hr
What does this tell us?
1-C: Renal and Hepatic Elimination
Renal Clearance & Urinary Excretion.
ClR = 1.864 L/hr
ClT = 10.42 L/hr
ClR / ClT = 0.1789
1-C: Renal and Hepatic Elimination
Renal Clearance & Urinary Excretion
If 17.89% of ClT
is determined by ClR
what is ClNR?
1-C: Renal and Hepatic Elimination
Renal Clearance & Urinary Excretion
If 17.89% of ClT
is determined by ClR
what is ClNR?
ClT = ClR + ClNR
ClNR = 10.4 – 1.8
ClNR = 8.55 L/hr
Renal Clearance of moxifloxacin
When evaluating Aminoglycoside Renal Clearance
(following IV dose with no metabolism and complete renal excretion)
we observed:
ClR = ClT
and therefore, ClNR = 0 L/hr
Calculations to complete
It would have also
beenExcretion
apparent rate
that vs. Time.
• Plot
the amount excreted in the
after infinite
time (Ae0-)
• urine
Calculate
K
would equal
theExcretion
dose.
• Plot
rate vs.
mid-point plasma conc.
… that an Excretion
Rate vs. Time
4. Calculate
Renalplot
clearance
had a slope5.proportional
to K
Calculate ke
6. Determine Ae0-
…that an Excretion rate vs.
point plasma
concentration
7. mid
Establish
some principles
had a slope equal to Renal
clearance (ClR).
of Elimination
But now, moxi has other routes of elimination…?
1-C: Renal and Hepatic Elimination
Renal Clearance & Urinary Excretion.
If 17.89% of ClT
is determined by ClR
ClT = ClR + ClNR
and
K = ke + knr
and K and ClT
are related by the
proportionality constant
-Volume
what is ke?
1-C: Renal and Hepatic Elimination
Renal Clearance & Urinary Excretion.
If 17.89% of ClT is determined by ClR
ClT = ClR + ClNR
and K = ke + knr
and K and ClT
are related by the proportionality constant - Volume
what is ke?
1-C: Renal and Hepatic Elimination
Renal Clearance & Urinary Excretion.
If 17.89% of ClT is determined by ClR
ClT = ClR + ClNR
and K = ke + knr
and K and ClT
are related by the proportionality constant - Volume
what is ke?
ClR
ke
----- = ----ClT
K
ClT = 10.42 L/hr and ClR = 1.864 L/hr
K = 0.0687 hr-1 and ke = 0.01242 hr-1
Renal Clearance of moxifloxacin
When evaluating Aminoglycoside Renal Clearance
(following IV dose with no metabolism and complete renal excretion)
we observed:
ClR = ClT
and therefore, ClNR = 0 L/hr
Calculations to complete
It would have also
beenExcretion
apparent rate
that vs. Time.
• Plot
the amount excreted in the
after infinite
time (Ae0-)
• urine
Calculate
K
would equal
theExcretion
dose.
• Plot
rate vs.
mid-point plasma conc.
… that an Excretion
Rate vs. Time
4. Calculate
Renalplot
clearance
had a slope5.proportional
to K
Calculate ke
6. Determine Ae0-
…that an Excretion rate vs.
point plasma
concentration
7. mid
Establish
some principles
had a slope equal to Renal
clearance (ClR).
of Elimination
But now, moxi has other routes of elimination…?
Renal Clearance of moxifloxacin
When evaluating Aminoglycoside Renal Clearance
(following IV dose with no metabolism and complete renal excretion)
we observed:
ClR = ClT
and therefore, ClNR = 0 L/hr
It would have also been apparent that
the amount excreted in the urine after infinite time (Ae0-)
would equal the dose.
However, now there is at least one other source of elimination
(kNR which is likely made up of kH (or kM1 and kM2) and kB
and since …
ClR
ke
----= ----ClT
K
If ke is determining how much drug appears in the urine then …
Renal Clearance of moxifloxacin
However, now there is at least one other source of elimination
(kNR which is likely made up of kH (or kM1 and kM2) and kB
and since …
ClR
ke
----= ----ClT
K
If ke is determining how much drug appears in the urine then …
Ae0-
ke
-------DoseIV = ----K
and
ClR
ke
Ae0-
----= ----= --------ClT
K
DoseIV
and all will have a ratio of ~ 0.1789 in this patient.
Renal Clearance of moxifloxacin
67.55 mg
Over the first 40 hours, 67.55 mg of moxi is collected in the urine.
Based proportion of drug being eliminated into the urine (ke/K)
the total amount expected in the urine would be
400 mg x 0.1789 = 71.56 mg.
Would 4.01 mg be expected to appear in the urine after 40 hr?
(40 hr  )
Renal Clearance of moxifloxacin
67.55 mg
Would 4.01 mg be expected to appear in the urine after 40 hr?
(40 hr  )
At 40 hours, 0.16 mg/L of moxi remains in plasma.
The estimated volume is 150.12 L.
Therefore the amount remaining in the body at 40 hours is:
0.16 mg/L x 150.12 L =
Renal Clearance of moxifloxacin
67.55 mg
Would 4.01 mg be expected to appear in the urine after 40 hr?
(40 hr  )
At 40 hours 0.16 mg/L of moxi remains in plasma.
The estimated volume is 150.12 L.
Therefore the amount remaining in the body at 36 hours is:
0.16 mg/L x 150.12 L = 24.6 mg
The amount that should appear in the urine (40 hr  ) would be:
0.1789 x 24.6 =
Renal Clearance of moxifloxacin
67.55 mg
Would 4.01 mg be expected to appear in the urine after 40 hr?
(40 hr  )
At 40 hours 0.16 mg/L of moxi remains in plasma.
The estimated volume is 150.12 L.
Therefore the amount remaining in the body at 40 hours is:
0.16 mg/L x 150.12 L = 24.6 mg
The amount that should appear in the urine (40 hr  ) would be:
0.1789 x 24.6 = 4.29 mg
Renal Clearance of moxifloxacin
When evaluating Aminoglycoside Renal Clearance
(following IV dose with no metabolism and complete renal excretion)
we observed:
ClR = ClT
and therefore, ClNR = 0 L/hr
Calculations to complete
It would have also
beenExcretion
apparent rate
that vs. Time.
• Plot
the amount excreted in the
after infinite
time (Ae0-)
• urine
Calculate
K
would equal
theExcretion
dose.
• Plot
rate vs.
mid-point plasma conc.
… that an Excretion
Rate vs. Time
4. Calculate
Renalplot
clearance
had a slope5.proportional
to K
Calculate ke
6. Determine Ae0-
…that an Excretion rate vs.
point plasma
concentration
7. mid
Establish
some principles
had a slope equal to Renal
clearance (ClR).
of Elimination
But now, moxi has other routes of elimination…?
Principals of Elimination
Equations
ClR
ke
ke
Ae0-
----- = ----- = ----- = --------ClT
K
k10
DoseIV
K = ke + kH + kNR
TBC = ClT = ClR + ClH + ClNR
ClH = ClM1 + ClM2
kH = kM1 + kM2
ClR = keV
Change in the Rate at which
drug appears in the urine
( Ex. Rate) is proportional
to concentration in serum
and slope is –K/2.303.
Slope of log Excretion Rate vs.
Time is proportional to K (-2.303)
the amount excreted in the urine
after infinite time (Ae0-)
equals ke/K
…that an Excretion rate vs. mid
point plasma concentration
has a slope equal to
Renal clearance (ClR).
Summary of Urinary Elimination
Change in the Excretion Rate at
which drug appears in the urine
[Slope (Log) Ex. Rate) vs.Time]
is parallel the slope of the
Concentration in serum vs. Time
Slope is –K/2.303.
This is true regardless of the
proportion of the dose excreted
into the urine
... as long as Ae0- >0
the amount excreted in the urine
after infinite time (Ae0-)
equals ke/K
Summary of Urinary Elimination
K is the overall rate constant
which determines the half-life.
ke determines the proportion of
the dose excreted into the urine.
Ae0-
ke
-------- = ----DoseIV K
the amount excreted in the urine
after infinite time (Ae0-)
equals ke/K
…that an Excretion rate vs. mid
point plasma concentration
has a slope equal to
Renal clearance (ClR).
Summary of Urinary Elimination
Second use of Excretion Rate:
If Excretion Rate is plotted
(not Log Excretion Rate)
vs. mid point plasma
concentration
…slope is equal to
Renal clearance (ClR).
Minimum requirement is a single
blood sample drawn at the mid
point of the urine
collection interval.
Summary of Urinary Elimination
What do you need to calculate K?
(i) At least 2 blood (plasma)
concentrations drawn
at known times.
(ii) At least 2 urine collections of
known intervals and time
since the dose.
Plot Log Excretion Rate
vs.
Time
Summary of Urinary Elimination
What do you need to
calculate ke?
(i) A complete urine collection
and a known dose
Ae0-
ke
-------- = ----DoseIV K
(ii) Through relationships with
other variables
ClR
ke
Ae0-
---- = ----- = ----ClT
K
DoseIV
Summary of Urinary Elimination
What do you need to
calculate ClR?
Minimum requirement is a single
blood sample drawn at the mid
point of the urine
collection interval.
If Urinary Excretion Rate is
plotted
vs. mid point plasma
concentration
…slope is equal to
Renal clearance (ClR).
Renal Function & Drug Clearance ClR
Remaining Slides
in this file
Filtration at the glomerulus. This is a
are for interest only.
function of a number of competing pressures.Creatinine clearance will
nd term.
be
covered
in
the
2
The hydrostatic pressure of blood is the overall
Renal Excretion is based on:
driving force filtering blood. Working against
this pressure is the osmotic pressure of the
blood to hold on to the fluid and the hydrostatic
pressure of the capsule. The result of these
completing pressures is a net ~10 mmHg
pushing fluid through the capsule and
into the proximal tubule.
In addition to filtration, there is active secretion,
in the proximal renal tubule and reabsorption
most likely in the distal tubules.
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Filtration at the glomerulus
Approximately 125 mL of protein
free filtrate is removed from the
blood every minute as it passes
through the glomeruli of the
kidneys. However, only drugs that
have a low molecular weight and
are not protein bound can pass through
the glomeruli [since protein is not filtered, drug bound
to protein is not filtered]. Since most drugs are small molecules,
only a high degree of protein binding will reduce the amount of
drug found in the protein free filtrate.
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Active secretion
Active secretion,
In addition to glomerular filtration,
some drugs may be actively
secreted into the proximal renal
tubules. Since secretion is an
active process, the secretion rate
does not appear to be influenced by
protein binding and is therefore,
generally felt to be “nonrestrictive”.
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Reabsorption
Reabsorption is a passive process
&may occur at any point in the
Tubule but is more likely occur
in the distal tubules as the urine
and the concentration of the drugs
within it, becomes more
concentrated. Reabsorption can
occur for any drug but it is more likely to occur for
unionized, non-polar drugs. As a result, the reabsorption
of weakly basic or acidic drugs may be dependant on urine pH,
which will determine the degree to which the drug exists in the
unionized state.
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Renal function is often estimated.
There are at least three
compounds that have been widely
used to estimate kidney function:
Inulin (MW ~ 5000);
total eliminated by GFR.
PAHA [para amino hippuric acid]
filtered and secreted.
Creatinine,
endogenous, filtered and secreted.
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Creatinine, easy & most popular.
Compoun used to estimate
renal function.It is an
endogenous end product
of muscle metabolism.
Calculation of CrCl.
To properly estimate creatinine
clearance a 24-hour collection of
urine is completed and the
creatinine measured. The amount
of creatinine excreted is determined
based on the urine volume.
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Calculation of CrCl
Creatinine Clearance (CrCl) is
then determined based on a single
serum creatinine measurement,
assuming that the measured
serum creatinine is the average
concentration of creatinine or
that the serum creatinine concentration
is constant over the 24-hr collection period.
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Calculation of CrCl…Example
Consider a patient with a
serum creatinine 1.1 mg/dL
and following a 24 hr urine collection
is found to have a creatinine
concentration of 1.4 mg/mL and
1250 mL of urine.
CrCl (mL/mIn = (100 x U x V ) / SCr x 1440
Where U is the concentration of creatinine in the urine in mg/dL,
V is the urine volume in mL and 100 is the conversion from dL,
and SCr is the creatinine concentration in plasma, in mg/dL.
1440 is the conversion to units of mL/min from mL/24 hrs
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Calculation of CrCl…Example
Consider a patient with a
serum creatinine 1.1 mg/dL
and following a 24 hr urine collection
is found to have a creatinine
concentration of 1.4 mg/mL and
1250 mL of urine.
CrCl (mL/mI) = (100 x U x V ) / SCr x 1440
= (100 x 1.4 x 1250) / (1.1 x 1440)
= 175000 / 1584
= 110.47 mL/min
= 110 mL/min
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Although creatinine is easy &
popular, as endogenous end
product of muscle metabolism,
creatinine production is directly
related to muscle mass.
Therefore, it is necessary to
correlate serum creatinine with
urinary creatinine clearance in males
and females of various ages.
There are many nomograms that describe a relationship
between serum creatinine and renal function.
One is the Cockcroft & Gault equation.
Cockcroft DW, Gault MH. Prediction of Creatinine clearance from Serum Creatinine. Nephron 1976; 16: 31-41.
Renal Function & Drug Clearance ClR
Renal Function & Drug Clearance ClR
Prediction of Creatinine Clearance from Serum Creatinine
DONALD W COCKCROFT & M HENRY GAULT
Nephron 1976; 16: 31-41.
Derived Equation (x 0.85 for females)
When SCr is reported in mg/100 mL CrCl is calculated in mL/min.
When Serum Creatinine is reported in μmol/L the equation is:
and CrCl is calculated in mL/sec and must be multiplied by 60 to yield mL/min.