PHAR7834 Pharmacokinetics

RENAL CLEARANCE

Sukyung Woo, Ph.D.

Associate Professor of Pharmaceutical Sciences
Email: sukyung-woo@ouhsc.edu

11/06/2017 1
 Pharmacokinetic Data Analysis
Dosing Information Sites of
Approaches PK Models System Route Frequency Measure
1 CM Linear Intravenous Single Plasma
kinetics -IV Bolus
Compartmental Multiple -IV Infusion
Analysis - 2 CM
- 3 CM Extravascular Multiple Urine
-Oral
Physiological Nonlinear
based Model kinetics

Non-compartmental
Analysis (NCA)
 Outline
Multiple Routes of Drug Elimination

Fraction of the Drug Excreted Unchanged

Calculation of Renal Clearance from Clinical Data

Renal Clearance Mechanisms

Effect of Renal Function on Renal Clearance and

Dose Adjustment

3
 Determination of Renal Clearance
Learning Objectives
Identify the major routes by which a drug may be eliminated from the body
Be able to define, use, and calculate the parameters:
U, fe , ke, km, and renal and non-renal clearance
Use the appropriate equations to calculate amount of drug excreted into
urine and rate of renal excretion
Identify contribution of different pathways to overall drug elimination
Determine renal clearance from clinical data
Be able to use fe, the fraction excreted, to calculate overall elimination rate
constants in patients with impaired renal function

4
 Why Urine Samples
Repeated blood samples may not be feasible from certain
patient populations, E.g., very young, pediatric patients
The apparent volume of distribution maybe so large that
plasma concentrations are too small to measure
To determine the role of metabolism and excretion pathways
in the elimination of a drug.
To determine the renal clearance and other pharmacokinetic
parameters.

5
Pharmacokinetic Jargon

Elimination = Metabolism + Excretion

Biliary
Excretion
Drug Elimination Renal Metabolism
Excretion of drug into bile, urine, Excretion

faces etc. (removal of the intact drug)

Biotransformation (i.e., metabolism)
Routes of elimination of
the top 200 drugs
Rate of Drug Elimination
CL = Total clearance (CL)
kel = Overall elimination rate constant
Elimination half-life (t1/2)

6
 Total Clearance (CL)
Total (Systemic) Clearance (CL)
The volume of blood (plasma) from which drug is completely and
irreversibly removed per unit time.
The sum of the clearances by each of the eliminating organs:

CL = CLR + CLH + CLother

Total Renal Hepatic Clearance by
Clearance Clearance Clearance other organs

Estimation of Total CL 40

F Dose
30
Cp (mg/L)
CL 20
AUC
10 AUC
also, CL kel V 0
0 4 8 12 16 20 24
Time (hr) 7
 Example of Urine Data
After an IV dose of 300 mg, total urine samples were collected after 2, 4, 6, 8, 10, 12,
18, 24 hours and assayed for drug concentration. The volume of each urine sample
was also recorded. The collected data are shown in the table below.

Time Urine Drug Conc. in How to calculate:

Interval Volume, Vu Urine, Cu 1) Amount of drug excreted over a time
(hr) (mL) (mg/mL) interval (U, mg)
Example:
0-2 50 1.666
U0-2 hr = Cu x Vu
2-4 46 1.069
= 1.666 mg/mL x 50 mL = 83.3 mg
4-6 48 0.592
2) Rate of excretion (U/t)
6-8 49 0.335
U/t = 83.3/2 = 41.65 mg/hr
8-10 46 0.210
3) Total amount excreted into the
10-12 48 0.116
urine (U)
12-18 134 0.047 =
18-24 144 0.009 =
=
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Drug Elimination Only by Renal Excretion
kel
Drug
in ke
plasma Drug
in
Urine
Amount of drug
in the body (X) Amount of
unchanged drug
excreted into urine
(U)

ke = first-order rate constant for urinary excretion

CL = CLR
Total Renal
clearance clearance

9
If the Drug is Eliminated ONLY by Renal
Excretion, then U = DoseIV

Dose = VCp0

Dose = U

U = total amount excreted into the urine

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 Elimination by Renal Excretion and Non-Renal
Routes: U < DoseIV
Total Clearance (CL)
Drug ke
CL = CLR + CLm in Plasma
(X)
Drug
in Urine
Total Renal Hepatic/Metabolic (U)
Clearance Clearance km = knr
Clearance
or CLnr : Non-renal CL Metabolite
in body
kmu
Metabolite
(M) in Urine
Elimination Rate Constant (kel) (Mu)
Similarly,
kel = ke + km
ke = first-order rate constant for urinary excretion
Km (knr) = first-order rate constant for metabolism (non-renal elimination)

11
fe = Fraction of Dose Excreted Unchanged
Drug in the Urine

fe =U/DoseIV
Cumulative amount
excreted into urine

187.5 mg =U

fe = 187.5 mg/250 mg = 0.75

Note. 0 fe 1 12
 Determination of Renal Clearance:
CLR = feCL
By collecting urine samples between time 0 and after
administration of an IV dose (DoseIV) of a drug,
we can determine:
U
fe fe = U/DoseIV
CLR CLR = feCL
CLnon-renal CLm = (1-fe)CL or CLm=CL - CLR

Time 0 and : 4-5 half lives > 95%

For derivation: Appendix I 13

 Contribution of Different Pathways to
Overall Drug Elimination
fe = Fraction of Dose Eliminated by Renal Excretion
U CLR ke
fe (CLR)
Dose IV CL kel
(CLm)
Thus, CLR = feCL and ke = fekel

1- fe = Fraction of Dose Eliminated by Metabolism

Thus, CLm = (1-fe)CL and km = (1-fe)kel Drug Elimination by Metabolism &
Excretion Pathways after IV dose

Note. kel = ke + km where,

V CL = total clearance = kel V
CLm = metabolic clearance = km V
CL = CLR + CLm CLR = renal clearance = ke V
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Plotting & Analyzing Urine Data to
Determine Renal Clearance
Case I. When urine is collected over successive time period after a dose
1. Cumulative Amount Excreted versus Time
2. Rate of Excretion versus Cp

Case II. Single-point determination (only under steady-state)

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 Determination of Renal Clearance:
CLR = Excretion Rate/Cp
Rate of Renal Excretion (dU/dt)
(CLR)
/

= =
(CLm)

Calculation of Rate of Excretion (U/t)

from experimental data
Amount collected

= over a time interval

Rate of Excretion
Time interval

(U/t)
Then,
/
= or =

Cp
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Case I

Determination of Renal Clearance from Urine Samples

Collected Over Successive Time Periods
Example of Experimental Data:
A 300-mg dose of Drug X (t1/2 = 3 hr) was administered intravenously to a healthy
subject. Urine samples were collected over various collection periods and the urine
was analyzed for unchanged drug. During the study, the plasma concentration was
measured at the midpoint of each collection period.
Urine Data Plasma Data
Time Interval Urine Volume, Drug Conc. in Urine, Tmid (hr) Cp
(hr) Vu Cu (Mid-point of Urine (mg/L)
(mL) (mg/mL) Collection Period)
0-2 50 1.666 1 10.56
2-4 46 1.069 3 4.29
4-6 48 0.592 5 2.23
6-8 49 0.335 7 0.82
8-10 46 0.210 9 0.45
10-12 48 0.116 11 0.17
12-18 134 0.047 15 0.04
18-24 144 0.009 21 0.003

[HW#16] 17
 Plotting and Analyzing Urine Data:
1. Cumulative Amount Excreted versus Time
U = Cumulative Amount Excreted Dose = 300 mg
Time Vu Cu U U
(hr) (mL) (mg/mL) (mg) (mg)
0-2 50 1.666 83.3 83.3 U = 200.1 mg

2-4 46 1.069 49.2 132.5

4-6 48 0.592 28.4 160.9
6-8 49 0.335 16.4 177.3
8-10 46 0.210 9.7 187
.
10-12 48 0.116 5.6 192.5 1. From urine data: = = .

12-18 134 0.047 6.3 198.8
2. From Cp-time data: CL = 7.89 L/hr
18-24 144 0.009 1.3 200.1
3. Calculate CLR and CLm:
= = . . /
fe = U/Dose U
= 5.26 L/hr
= . . = . /
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 Plotting and Analyzing Urine Data:
2. Rate of Excretion versus Cp
U/t = Rate of Excretion
Time Vu Cu U t U/t Tmid Cp Slope = CLR
(hr) (L) (mg/L) (mg) (hr) (mg/hr) (hr) (mg/L)

0-2 50 1.666 83.3 2 41.7 1 10.56

2-4 46 1.069 49.2 2 24.6 3 4.29
4-6 48 0.592 28.4 2 14.2 5 2.23
6-8 49 0.335 16.4 2 8.2 7 0.82
8-10 46 0.210 9.7 2 4.8 9 0.45
10-12 48 0.116 5.6 2 2.8 11 0.17 1. From urine data: = . /

12-18 134 0.047 6.3 6 1 15 0.04 2. From Cp-time data: CL = 7.89 L/hr
18-24 144 0.009 1.3 6 0.2 21 0.003 3. Calculate fe and CLm:

/
= . . = . /
= =
.
= = = .
. 19
 Summary:
Methods of Determining Renal Clearance (CLR)
Cumulative Amount Excreted
versus Time
Key info. U U/t
Disadvantage Not suitable for a drug with
long half-life (e.g., difficulty
in collecting urine samples
long enough)
Calculation of is affected
by missing samples
especially early time
Advantage More suitable with drugs
which have short half-lives
Rate of Excretion versus Cp
Sensitive to the error present
in "real" data
This method can be difficult to
use with drugs which have
short half-lives (e.g., difficulty
in frequent sampling)
Does not require to collect
urine samples for longer
duration (e.g., 5-7 half-lives)
Less sensitive to missing
sample
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Application: Calculation of CLR & CLm
The following data were obtained by collecting urine after IV
administration of an antibiotic at a dose of 500 mg in a patient with
normal renal function. It is known that the drug is eliminated by hepatic
metabolism and by urinary excretion. The elimination half-life was 3.85
hours. The total clearance was 3.6 L/hr.

(a) Calculate the drugs renal clearance

(b) Calculate the drugs non-renal clearance

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Application: Calculation of CLR & CLm
Solution:
The total clearance was 3.6 L/hr. Since urine samples were collected up to 48 hr,
which is more than 5 x half-lives (3.85 hr), the total cumulative amount of drug
excreted in urine (350 mg; from the graph) can be considered as
The fraction of the dose excreted unchanged in the urine (fe)
U 350 mg
fe 0.7
Dose IV 500 mg

The renal clearance (CLR) for this patient.

=
= . . / = . /

The metabolic clearance (CLm) for this patient

=
= . . = . /
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Case II

Single-Point Determination of Renal Clearance

Should be used only under steady-state condition, when Cp is constant

This is the method used to calculate the clearance of creatinine
Experimentally,
1. The steady-state plasma concentration (Cp) is determined
2. One large urine sample (rather than individual urine samples) is collected
over an extended period of time (4-5 half-lives)
3. The rate of excretion (/) over the entire collection period is calculated

/ Rate of renal excretion

= =
Plasma conc.

(from Dr. Lewiss Lecture)

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 Application: Calculation of CLcr
The creatinine clearance is to be determined in a female patient. Her urine was
collected over 24 hr and a serum concentration measured at the midpoint of the
urine collection period. The urine volume collected was 1050 ml and the
creatinine concentration in urinary sample was 1.14 mg/ml. The midpoint
creatinine serum concentration was 1.0 mg/dl. Determine the creatinine
clearance using the urine/plasma data.

Amount of creatinine excreted in urine (U): 1.14 mg/ml x 1050 ml = 1197 mg

Rate of renal excretion (U/t): 1197 mg/24 hr = 49.9 mg/hr
Renal clearance:

/ . /
=
=
/
= . /

= . /

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 Renal Clearance Mechanisms
Learning Objectives
Understand the factors that control renal clearance: glomerular filtration,
tubular secretion, and tubular reabsorption

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Nephron: Anatomy and Function
Renal blood flow = 20-25% of
cardiac output or 1.1 1.2
L/min; effective renal plasma
flow = ~600 ml/min

~10% is filtered at the

glomerulus (120 ml/min) =
Glomerular Filtration Rate
(GFR)

Most of water is reabsorbed,

resulting in a urine flow of only
1-2 ml/min

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 Renal Clearance by Excretion Processes

= +

where CLRF = clearance by renal filtration

CLRS = clearance by renal secretion
TR = tubular reabsorption (i.e., amount
of drug that is filtered and secreted
that is reabsorbed)

= 27
 CLRF = Clearance by Renal Filtration
Glomerular Filtration Rate (GFR) = rate at which plasma water is filtered;
GFR = 120 ml/min
Only free (unbound, ) drug is filtered.
If drug is highly bound in plasma, renal extraction of a drug by this
mechanism alone is low

= ( fu is the fraction unbound)

Small molecules (MW < 2000) Molecular size and glomerular filtration of proteins
are completely filtered. Protein MW (g/mole) Cfiltrate/Cp
Insulin 6,000 0.89
Myoglobulin 16,900 0.75
Bence Jones 44,000 0.08
Albumin 69,000 0.001
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 CLRS = Clearance by Tubular Secretion
Secretion = active transport from blood to lumen of nephron, facilitates
excretion into urine (i.e., increasing renal CL)
Saturable (concentration-dependent)
p-aminohippuric acid (PAH) is extensively secreted;
thus, PAH CLR = ~ renal plasma flow rate of 425- 600 ml/min

( CLisec )
=
+ ( CLisec )

fU = fraction unbound
QR =renal blood flow
CLisec= intrinsic secretion clearance

Secretion is apparent when CLR > fuGFR

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 Tubular Secretion: Drug Interactions

Can be inhibited by other

drugs secreted by the same
mechanism Plus
Probenecid
E.g., inhibition of penicillin
excretion by competition with
probenecid
control

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 TR = Tubular Reabsorption:
from Tubular Fluid to Blood

= +

Active reabsorption
e.g., Glucose, amino acids, vitamins, sulfate, phosphate, ascorbic acid, etc

Passive reabsorption along a concentration gradient

Lipid solubility
pKa (drug in the unionized form is readily reabsorbed)
pH of urine: average pH is 6.3 (4.5 8.0)
acetazolamide, sodium bicarbonate: pH
Ascorbic acid, ammonium chloride: pH
Urine flow rate
urine flow rate: concentration gradient between tubular fluid and blood
residence time at site of reabsorption

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Tubular Reabsorption: Urine pH
Salicylic Acid Methamphetamine

Passive reabsorption is most important for:

When urine is acidic, weak acid drugs (pKa 3-7.5) tend to be reabsorbed.
When urine is more alkaline, weak base drugs (pKa 6-12) are more
extensively reabsorbed
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 CLR of Phenobarbital

In the case of a drug overdose it is possible to increase the excretion of some drugs by
suitable adjustment of urine pH. For example, in the case of pentobarbital (a weak acid)
overdose it may be possible to increase drug excretion by making the urine more
alkaline with sodium bicarbonate injection.
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Interpretation of the Renal Clearance
Drug = Comments
(mL/min) (mL/min)
Atenolol 170 0.95 120 x 0.95 = 114 Some tubular secretion

Ciprofloxacin 500 0.6 120 x 0.6 = 72 Significant tubular

secretion
Theophylline 10 0.5 120 x 0.5 = 60 Significant tubular
reabsorption

What renal clearance mechanisms are involved?

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 Effect of Renal Function on Renal
Clearance and Dose Adjustment
Learning Objectives
Understand the influence of renal disease on drug elimination
Calculate suitable drug dosage regimen for patients with impaired renal
function

35
 Application:
Calculation of Total Clearance for a Patient with
Reduced Renal Function
After IV administration of an antibiotic at a dose of 500 mg in a patient
with normal renal function, 70% of the dose was excreted unchanged in
the urine. It is known that the drug is eliminated by hepatic metabolism
and by urinary excretion. The elimination half-life was 3.85 hours. The
total clearance was 3.6 L/hr.

What is the total clearance (CLpt) for another patient with 50% reduced
renal function of the normal subject?
Solution:

Recall: fe = 0.7
= +
CLR = 2.52 L/hr
CLm = 1.08 L/hr = . + . = . /

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 Effect of Renal Function on Renal Clearance

When the following drugs are used in a patient with normal renal function:
Vancomycin is eliminated almost completely in the kidneys (fe = 0.95),
and its elimination half-life is 6 hr.

Erythromycin (fe = 0.15) has the elimination half-life of 1.2 hr.

What is the elimination half-life (or kelpt) for vancomycin and erythromycin
for a 50-year-old patient with severely impaired renal function (1/10 th of
the normal kidney function)?

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Effect of Renal Function on Drug Elimination

Example: Vancomycin
Normal Subject
fe = 0.95 (Dose 500 mg every 6 hrs; V = 33L)
kel = 0.116 hr-1 (t1/2 = 6 hr)

Calculate ke and km for normal subject:

ke = kel fe = 0.116 x 0.95
= 0.110 hr-1 Renal failure
km = kel (1 - fe)
= 0.116 x 0.05 = 0.006 hr-1

Renal Failure Patient

1/10 th of the normal kidney function
kept = 0.011 hr-1
kelpt = kept + km
= 0.011 + 0.006 hr-1 = 0.017 hr-1 = [ ]
(t1/2 = 41 hour) (from Dr. Lewiss Lecture)
38
Effect of Renal Function on Drug Elimination

Example: Erythromycin
Normal Subject
fe = 0.15
kel = 0.58 hr-1 (t1/2 = 1.2 hr)

Calculate ke and km for normal subject:

ke =fe kel = 0.58x0.15 =0.087 hr-1
km = (1 - fe) kel = 0.58 x 0.85 = 0.493 hr-1

Renal Failure Patient

1/10 th of the normal kidney function

kept = 0.009 hr-1

kelpt = kept + km
= 0.009 + 0.493 hr-1 = 0.502 hr-1
(t1/2 = 1.4 hour)

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Relationship Between CLcr and Overall
Drug Elimination (kel or CL)
kel = knr + b CLcr

Examples:

Intercept = knr

Estimation of kel in a Patient using CLcr: Kanamycin

Patient with normal renal function (CLcr = 120 ml/min):
kel = 0.01 + 0.0024 x 120 = 0.298 hr-1

Patient with renal failure (CLcr = 10 ml/min)

kel = 0.01 + 0.0024 x 10 = 0.01 + 0.024
= 0.034 hr-1 40
 Dosage Regimen Adjustment for Patients with
Poor Renal Function
Example: Kanamycin 250 mg IM every six hours
(250 mg IM every six hours; F=1; V=13.3 L)
Renal patient
Normal subject: kel = 0.3 hr-1 (t1/2 = 2.3 hr)

ss
kel
FD e
ss
C min
- kel = 3.7 mg/L (ka >> kel)
V (1 - e )

Renal failure patient: kel = 0.034 hr-1 ( t1/2 = 20 hr)

( > 35 mg/L; the maximum

Dosage adjustment
should be made!
recommended Cp)
We could consider:
a) changing the dose
b) changing the dosing interval
or c) changing both the dose and the dosing interval 41
 Dosage Regimen Adjustment for Patients with
Poor Renal Function (contd)
Renal failure patient: kel = 0.034 hr-1 ; = 10.4 mg/L
a) Altered dose ( = 6 hr)

Cpmin = 9.3 mg/L

b) Altered dose interval (Dose = 250 mg)

Cpmin = 3.7 mg/L

c) Altered dose and interval ( = 24 hr)

Cpmin = 6.7 mg/L

42
Appendix I

Determination of Renal Clearance

Rate of Renal Excretion (dU/dt) (CLR)

= (CLm)

Rearrange for CLR

/ Rate of Excretion
= =
Plasma conc.

integration of above equation

Recall: fe =
= =


CL =

43
Appendix II
Summary:
Relationship Among , ,
Excretion Metabolism Total Sum

Contribution 1 1
(Fraction, )

Clearance + =
( )
= = (1 )

First-order rate + =
constant = = (1 )
( )
CL, k, & V = = =

44