Quantitative Aspects :

Time course of drug in the body.

Clinical Pharmacokinetics

Prof. H.Achmad Basori

Departemen Farmakologi
FK UNAIR
 General Pharmacology
PHARMACOKINETIC
II. QUANTITATIVE ASPECT
Time course of drug in the body.

Prof. H.Achmad Basori

Departemen Farmakologi dan Terapi
FKUA
 Tissue Receptor
EFFECT
K+ Na+ Ca2+

-protein A A

-fat

I.V
Liberation Blood
Specific barrier
PROTEIN
FREE DRUG BOUND
DRUG Renal
Absorption
GI tract
METABOLITE
-Aktif
-Tidak aktif
Enterohepatic
circulation Glomerular filtration
Liver Tubular secretion
-Microsome Passive reabsorption
-Non microsome
BIOTRANSFORMATION
Plasma Level vs Time Plots
I.V

P.O, i.m
Blood Flow to organs

Lung

Adipose

Bone

Brain

Venous Blood Heart

Arterial Blood
Kidney

Muscle

Skin

Liver
Spleen
Portal
Vein
Gut

IV PO
10
Aliran darah menuju organ
5000 ml/minLungs
1350 ml/minLiver
1100 ml/minKidneys
750 ml/minMuscle
700 ml/minBrain
300 ml/minSkin
200 ml/min Fat
Primary Pharmacokinetics
Parameter
Clearance (Cl)
Half-lives (t )
Distribution Volumes (Vd)
Bioavailability ( F )
AUC

Secondary Pharmacokinetic Parameter

Vss, Css av, Css min, Css max, CL-h, CL-
R,dll
One Compartment Open Model Intravenous
Administration

The one compartment model offers the simplest way to

describe the process of drug distribution and elimination
.in the body
i.v. Blood kel
(Vd)
Input Output

When the drug is administered i.v. in a single rapid

injection, the process of absorption is bypassed
16
 Intravenous Administration
Difference in plasma conc-time curve

Cp

Time

Intravenous Administration
17
One Compartment Open Model Intravenous Administration

18
 FIRST-ORDER KINETICS
Kecepatan eliminasi merupakan first order reaction
kel is a first-order rate constant with a unit
.of inverse time such as hr-1

19
Kinetika eliminasi obat dari tubuh

ZERO-ORDER KINETICS
Process occurs at a constant rate. 1
Rate is independent of concentration. 2

FIRST-ORDER KINETICS
Process occurs at a decreasing rate. 1
Rate is proportional to concentration. 2
t Order Elimination
Fraksi obat yang dihilangkan dari tubuh
per satuan waktu adalah constan
Jumlah obat yang dieliminasi dari tubuh
per satuan waktu adalah tergantung
pada jumlah obat didalam tubuh
Hampir semua obat dieliminasi dari tubuh
menurut reaksi tingkat pertama ( first
order reaction)
Zero order
jumlah obat yang dieliminasi
persatuan waktu adalah konstan
(Theophylline, Aspirine, Phenytoin)
:First-order process
dC/dT = kC (constant fraction)

:Zero-order process
dC/dT = k (constant amount)

:Capacity limited process

; low C, first-order
high C, zero-order
 Kinetika Obat Dalam
Tubuh
Zero Order First Order Kinetics
Kinetics
Rate = k C
Rate = k C = Co e-kt
C = Co - kt
C vs. t graph tdk
linear, menurun secara
C vs. t graph
. exponential
LINEAR
Log C vs. t graph
. linear
 First order Zero Order
ate of elimination depends rate of elimination is constant
n plasma concentration and independent of plasma
concentration
ting the data Semi-log paper

25
Conc. Vs. time plots

C = C o - kt ln C = ln Co - kt
 INTEGRATED EQUATIONS
The rate of change of drug plasma conc over time
:is equal to

dC p
kel C p
dt
Reaksi tingkat 1 dan tergantung k el
27
First Order Elimination (Linier)

dC/dt C
dC/dt = kC
Plasma concentration

lnC = lnC0 Kel t

C = C0 . e Kel t
ln = 2.3 log
logCt = logC0 Kel t
2.3
y = b a.x
 lnCt = lnC0 Kel.t
logCt = logC0 - Kel

2.303
Ln = 2.3 log
Bila Ct = Co,
Kel.t = 0.693.
t1/2 = 0.693/Kel

t : the time for the plasma concentration to

reach half the original, i.e., the half-life of
elimination.
Useful in estimating:
- time to reach steady state concentration.
- time for plasma concentration to fall after dosing is
stopped.
 10000

First Order Elimination

1000

100
Concentration
Log Plasma

10

1
0 1 2 3 4 5 6
Time
HALF LIFE AND PERCENT OF
DRUG REMOVED
Number of Percent of Drug Percent of Drug
Half-lives Remaining Removed
0 100 0
1 50 50
2 25 75
3 12.5 87.5
4 6.25 93.75
5 3.125 96.875
Half life and onset of action using
maintenance dose and no loading dose

Number of Percent of final

Half-times steady state concentration
0 0
1 50
2 75
3 87.5
4 93.75
5 96.875
Contoh : kalau diberikan dengan interval = t

Half life hours steady state

Lignocaine 2 8 hours

Valproate 6 24 hours

Digoxin 32 6 days

Digitoxin 161 28 days

t1/2 dapat digunakan untuk memprediksi berapa lama
obat dieliminasi dari plasma from plasma.

1. 2. 3. 4. 5.
10
50 75 87.5 94 97
Conc. (mg/L)

7.5 5 percent eliminated %

5 t1/2 = 2 hours
2.5 C = C0 . e Kel t
2.5 1.25
0.625
0
0 2 4 6 8 10
time (h)
t1/2 dapat vdigunakan untuk memprediksi berapa lama
waktu yang diperlukan dari mulai pemberian dosis
sampai mencapai kedaan tunak (steady state) pada
pemberian dosis ganda atau continuous i.v. infusion.

No. of t1/2 Concentration achieved

(% of steady conc.)
1 50
2 75
3 87.5
4 94
5 97
4 -5 x t
Extravascular Administration
Area Under TheCurve (AUC)
AUC = Jml Obat dalam tubuh
C.Dt = AUC
0
100 I.V
AUC = Dihitung menurut
Concentration

Trapezoidal Rule

0
Onset of action Time
 C = C0 . e- k.t
monoexponential decay
AUC is an integral
AUC = Dose / (V . kel)
AUC = Dose / CL
CL= Dose / AUC (i.v.)
CL= F. Dose / AUC

The AUC value is very useful for calculating the amount of drug
which reaches the systemic circulation )the absolute bioavailability F(
after administration of different drug products.
 PHARMACEUTICAL ALTERNATIVES
(the same API,diff chem form, (ester or salt), dosage form/strength)

PHARMACEUTICAL EQUIVALENTS
(The same API ,dosage form, route,identical in strength or conc)))

The same Bioavailability

No RCT
WHO, 1998
BIOEQUIVALENCE
(The same route, Pharm.Equiv, dosage form, labeled, GMP)

THERAPEUTIC EQUIVALENT

GENERIC SUBSTITUTION
BA Measurement
Bioavailability means the rate and extent to which the
`
active
` ingredient or active moiety is absorbed from a drug
product and becomes available at the site of action
(FDA Guideline,2003).
Absolute bioavailability (F):
Cmax
AUCextravascular Doseint ravenous
F
Ka AUCint ravenous Dose extravascular
Concentration

Relative bioavailability (Frel)

AUC extravascular1 Doseextravascular 2
MBC Frel
AUC extravascular 2 Doseextravascular1
MIC
AUC Study Compound
Reference Compound

Tmax Time
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER
Web site. Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic
Equivalence-Related Terms. Accessed September 29, 2003.
 Volume of Distribution (Vd)
Is the volume in which the drug is dissolved in the
.body
Example: 1 gram of drug is dissolved in an unknown
volume of water. Upon assay the conc was found to be
?1mg/ml. What is the original volume of the solution
V = Amount / Conc = 1/1= 1 liter
Also, if the volume and the conc are known, then the
original amount dissolved can be calculated
Amount = V X Conc= 1X1= 1 gram

47
Single-compartment model

C
ka ke

Absorption Vd Elimination
VOLUME OF DISTRIBUTION
Extracellular
Vascular Extravascular Intracellular

3L 9L 28 L

4% BW 13% BW 41% BW

Components of Total Body Water

 Penentuan harga Vd

Vd = Dose i.v /C0

Extrapolated estimate of C0

Dose D
Vd
B

Log Conc Cp C p

time
 Perhitungan Vd
dosis 1000 mg suatu obat diberikan ke
pasien secara i.v. Kemudian kdr dlm darah
: ditentukan
100 100 mg/L hr 2

67 mg/L hr 4

mg/L
45 mg/L hr 6
Vd=Dosis/Co
10
2 3 4 5 6
Co= 150 mg/L
Time (h)
Vd=1000/150 L= 6.7 L
For One Compartment Model with IV
:Administration
Cpo

Dose DB
Vd

Cp Cp

52
Apparent volume of distribution (Vd)

amount of drug in body

Vd
plasma drug concentrat ion
Vd =
VOLUME OF DISTRIBUTION FOR SOME DRUGS
Dose/C0
DRUG Vd (L)
cocaine 140
clonazepam 210
amitriptyline 1050
amiodarone ~5000
: Volume compartments tubuh dalam hubungannya dengan VDD

Total body water 0.6 L/kg BW

Intracellular water 0.4 L/kg BW
Extracellular water 0.2 L/kg BW
Plasma 0.04 L/kg BW
VDD 0.05 L/kg the drug remains in the blood (heparine)
VDD 0.1-0.3 L/kg distribution from blood into extracellular
fluid (gentamicin - polar drugs).
VDD 0.6 L/kg distribution from blood into intracelular
and extracellular fluid (methotrexate)
VDD >>0.6 L/kg distribution intracellularly and high
binding in tissues (amiodarone 350
L/kg)
 Vd beberapa obat obat

Drug Liters/Kg Liter/70 Kg

Chloroquine 94 250 6600 - 17500

Nortriptyline 21 1500

Digoxin 7 500

Lidocaine 1.7 120

Theophylline 0.5 35

Tolbutamide 0.11 8
 Perhitungan harga Vd dari AUC

dDB/dt = -kelD = -kelVdCp

dDB = -kelVdCpdt
dDB = -kelVd Cpdt
Cpdt = AUC
AUC = Dose / kelVd
Dose Model
Vd Independent
kel [ AUC] Method
58
Apparent Vd
It is called apparent because it does not have any
physiological meaning. Drugs that are highly lipid
soluble, such as digoxin has a very high Vd )600
liters(, drugs which are lipid insoluble remain in
.the blood and have a low Vd
For digoxin, if that were a physiological space and
I were all water, that would weigh about 1320 lb
.)599 kg(

59
 Volume of distribution (Vd)
Lipid-insoluble drugs
Vd kecil
Distribusi obat hanya di plasma dan
cairan interstitial
Lipid-soluble drugs
Vd besar
Distribusi obat menuju semua
kompartemen
Vd melebihi volume cairan tubuh total
Obat terakumulasi diluar plasma
fat
Terikat kuat dengan jaringan
Apparent Volume of Distribution
(Vd)

Small Vd
Low tissue binding
Large Vd
Drug tightly bound
 :Guna Vd
Vd dalam hubungannya dengan target concentration. 1
:CT, dapat digunakan menghitung loading dose DL
DL = VD . CT

2)Menentukan perkiraan jumlah obat dalam tubuh

Amount in the body = Vd . Cactual, measured

Untuk hemoperfusi. Biasanya obat dengan harga Vd) 3

besar, kurang efektif dari pada obat dengan Vd kecil
Perhitungan regimentasi dosis.4
Mengetahui distribusi obat, displacer, dll.5
 Clearance (CL)
Clearance Obat adalah ratio dari the rate of
elimination melalui semua rute thd the
.concentration of drug in plasma
CL = Rate of eliminination [mg / h ]
C in plasma [mg /L ]
Volume/Time [L/h] atau unit BB [l/h/kg]

Rate of eliminination = CL x C in plasma

(Amount / Unit of time)= (Volume / Unit of time) x Cin plasma
Unit: Volume/Time [L/h]
Kecepatan eliminasi = Kel x Jml Obat dlm tubuh
Kec eliminasi = CL x kadar dlm Plasma

Kel x Jml obatdlm tubuh = CL x Koncentrasi

Kel = CL/Vd

0.693/t1/2 = CL/Vd

t1/2 = 0.693 x Vd/CL

half-life eliminasi dari suatu obat dari tubuh
Tergantung pada pada clearance dan volume
distribusi

t1/2 berbanding lurus dgn Vd

t1/2 berbanding terbalik dengan CL
t1/2 = 0.693 x Vd/CL
Pharmacokinetics of Drugs by
Intravenous Infusion
ONE COMPARTMENT MODEL
WITH IV INFUSION
This can be obtained by high
degree of precision by infusing
drugs i.v. via an infusion

67
PK of Drug Given by IV
Infusion
Zero-order Input (infusion rate, R)
First-order Output (elimination)

68
Integrated equation
Zero-order Input (infusion rate, R)
First-order Output (elimination)

dC p
R kel C p
dt
,By integration

R k el t
Cp )1 e (
69
Vd k el
 Stopping the Infusion
Stopping the infusion before reaching steady state

Infusion stops

70
 Stopping the Infusion
Equations

R k el t
Cp )1 e (
Vd k el

k el t
Cp C e 0
p

71
Steady State Concentration
IV Infusion until reaching Css

R
C ss
Cl

72
 Steady State Concentration
(Css)
Theoretical SS is only reached after an infinite infusion
time
R
Cp )1 e (
Vd k el
R R
C ss
Vd k el Cl
Rate of elimination = kel Cp
73
Steady State Concentration (Css)
Rate of Infusion = Rate of Elimination
Kec infusion )R( tetap. Sedang
rate of elimination meningkat
Waktu mencapai SS berbanding langsung
dengan half-life
, Setelah 1 half-life, Cp : 50% dari CSS
setelah 2 half-lives, Cp : 75% dari Css
.
74
Steady State Concentration (Css)
In clinical practice, the SS is considered to be
reached after five half-lives

75
Increasing the Infusion Rate
If a drug is given at a more rapid
infusion rate, a higher SS drug
concentration is obtained but the time
to reach SS is the same.

76
Loading Dose plus IV Infusion
DL is used to reach SS rapidly

DL kel t R k el t
Cp e )1 e (
Vd Vd k el
DL kel t R R kel t
Cp e e
Vd Vd k el Vd kel

R DL kel t R kel t
Cp e e
Vd k el Vd Vd k el
77
 Loading Dose plus IV Infusion
DL with IV infusion at the same time
Loading k el t DL kel t
dose C1 C e

p e
Vd

IV R k el t
infusion C2 )1 e (
Vd k el
DL + IV DL kel t R k el t
infusion Cp e )1 e (
Vd Vd k el
78
Reaching SS Immediately
Let , DL = CssVd But, CssVd = R / kel

R DL kel t R kel t
Cp e e
Vd kel Vd Vd k el

Therefore, if a DL = R / kel is given SS will be

R but R
reached immediately
Cp C ss
Vd k el Vd k el
79
Reaching SS Immediately
IV DL equal to R /kel is given, followed by IV
infusion at a rate R

80
DL + IV Infusion

81
 Contoh

J.K.(TBW = 90 kg)was admitted to the ICU for

pneumonia caused by Gram-negative bacteria.
Calculate the loading dose of tobramycin for this patient
to achieve the target average concentration of 4 mg/l.
Tobramycin VD is 0.2 l/kg of TBW.

Loading Dose = ?
Loading Dose = 0.2 . TBW . Concentration Loading
Dose = 0.2 . 90 . 4 = 72 mg
Penderita asthma non-smoker, target conc Theophylline
10 mg/l Untuk mencegah serangan acute asma.
Harga tabel = Cl Theophylline =2.8 l/h/70 kg
Obat diberikan secara intra vena ( F=100 %) p
Dosing rate = CL.Target Concentration
= 2.8 l/h/70 kg x 10 mg/l
= 28 mg / h / 70 kg
Kecepatan infusi pada penderita = 28 mg/h/70 kg
Bila serangan akut asma sudah ditanggulangi, klinisi
Ingin mempertahankan kadar Theophylline dalam darah
Dengan memberikan Theophyl SR p.o, setiap 12 jam.
Sesuai dengan tabel F p.o=0.96%.
Dosis pemeliharaan= Dosing rate/ F .Dosing interval
= 28 mg/h/0.96. 12 jam
= 350 mg
Intravenous infusion

Pada keadaan steady state (tunak)

rate of infusion = rate of elimination
= Css.Clearance

Css (plateau)

Cp C = Css(1- e-kt)
Time to 90 % of Css = 4 t1/2

time
Fase ini ditentukan oleh Tingginya kadar tunak (plateau)
rate of elimination Ditentukan oleh rate of infusion

2X mg min-1

Cp X mg min-1

time
The time to reach steady state is ~5 t1/2s

Css

Concentration due to repeated

doses

Concentration due to a single dose

1000 mg, bolus injection 10 menit

1000 mg, 3 h infusion

500 mg, 3 h infusion

MIC
Multiple dosing -
Intravena
Pada pemberian dosis ganda kdr dalam
drh meningkat dengan cepat pada saat
pertama kdr dlm darah naik dgn cepat
lambat dan mencapai plateau
( kadar tunak),dimana :
rate of administration = rate of
elimination . steady state dicapai
Pada steady state:
Dose (Rate of Administration) = clearance x
plasma conc.
 Dosing rate =Rate of elimination
(pada intermittent doses )

CSS max: maximum concentration of

steady state Peak C

Css min: minimum concentration of

steady state

Peak Time: It is a time achieving the

CSS max
 Berdasarkan hubungan antara t1/2 dengan dosing interval
) ,maka dapat digunakan untuk memprediksi derajad
accumulation dari obat didalam darah. Makin panjang t1/2
dan makin pendek , maka obat makin mengalami
accumulasi.

t1/2 Moderate accumulation during

dosing 2-times)
< t1/2 Significant accumulation during
dosing (> 2-times)
> t1/2 Insignificant accumulation during
dosing (< 2-times)
 t1/2 (hubungan antara t1/2 dan interval t) dapat digunakan untuk
memprediksi derajad fluktuasi konsentrasi obat dalam interval
dosis .

t1/2 Css,min levels at steady state are aprox.

50% of Css,max. Moderate fluctuation.

< t1/2 Css,min levels at steady state are more

than 50% of Css,max. Small fluctuation.

> t1/2 Css,min levels at steady state are less

than 50% of Css,max. Wide fluctuation.
The effect of loading dose immediate efficacy
LD
MD
 Single dose
Plasma Concentration Loading dose

Therapeutic
level

Repeated doses
Maintenance dose

Time
Multiple short i.v. infusions dari Amikacin:
1/2= 8 h 16 h
kecepatan dosis tetap, tetapi interval berubah , t 1/2

300 mg, 8h 600 mg, 16h

50
40
concentration in plasma

30
(mg/L)

20
10
0
0 12 24 36 48 60 72 84 96

time since start of dosing (h)

Multiple short i.v. infusions of amikacin:
the rate of dosing is constant but
interdose interval is changing, t1/2= 6 h
300 mg, 8h 150 mg, 4h
50
40
concentration in plasma

30
(mg/L)

20
10
0
0 12 24 36 48 60 72 84 96
time since start of dosing (h)
Loading dose
Diberikan pertama kali untuk mencapai Css
dengan cepat

Loading dose = Jumlah obat didalam tubuh

yang mencapai Css setelah diberikan
loading dose

Loading dose : dosis awal yang menaikkan

kadar obat dalam darah untuk mencapai
konsentrasi sasaran

Umumnya diberikan sebesar 2 x dosis

maintenance dan interval = t
 C SS

T
Css=1.44t1/2D/(Vd )
Merubah interval dosis 0.5t1/2, t1/2,2t1/2, ;Dosis tetap,
, Css tetap
Tss berubah

C
Css=1.44t1/2D/(Vd )
Merubah dosis 2D, D, 0.5D; t1/2 tidak berubah,
Css berubah , Tss tidak berubah
5. t1/2 dapat digunakan untuk memprediksi berapa waktu
yang diperlukan bila konsentrasi obat turun pada waktu
tertentu . Pada over dosis dan pengaturan dosis

t = t1/2 . ln(C1/C2) / 0.7

 Rate of elimination
Elimination which follows first-order
kinetics: semi-log graph.
t 1/2 = 0.693/ kel

kel dihitung melalui the

linear-regression analysis
Multiple dosing - Intravena
Pendekatan perhitungan Clearance :
Clearance adalah volume plasma yang
secara sempurna dibersihkan dari obat per
unit waktu melui semua rute ( the liver, the
kidney).
Volume darah yang dibersihkan dari obat
.dari organ tertentu per satuan waktu
Clearance merupakan konsep yang lebih
fisiologik dari t 1/2 atau kel, karena
berdasarkan blood flow rate
Clearance bervariasi dengan berat
 Clearance (CL)
Clearance has an additive character: it is the
sum of clearences in all eliminating organs

CL = CLRENAL + CLHEPATIC +CLpulmonary ...other

renal + nonrenal
 Organ Clearance

Carterial Cvenous
Organ of elimination
Q
plasma flow

Elim. rate = Q(Carterial Cvenous) (mass/time)

: E = Single pass extraction fraction

E = Elim. flux/ input flux = (Carterial Cvenous)/Carterial

Clearance Elim. rate/C (vol/time)

Clearance = EQ
 Drug in Plasma

10g/m Organs of <

l drug 10g/ml
elimination

CL = 500g/min
500g
per min 10g/ml

= 50ml/min
HEPATIC CLEARANCE
1. Mass Balance

Q x CA Q x CV

Q(CA - CV)
Rate of Extraction
HEPATIC CLEARANCE
2. Mass Balance Normalized to Rate of Entry

1 1-E

E
Extraction Ratio
HEPATIC CLEARANCE
3. Mass Balance Normalized to CA

Q Q(1 E)

QxE
Clearance
Ingat CL = QE, maka
CL H = Q HE
CLH = hepatic clearance
QH = hepatic blood flow
E = hepatic extraction ratio
QH - from 1.0 to 1.5 L/min
E ranges from 0 to 1
HEPATIC EXTRACTION RATIO OF
REPRESENTATIVE DRUGS
Low (<0.3) High (>0.7)
Antipyrine Lidocaine
Diazepam Meperidine
Phenylbutazone Propoxyphene
Theophylline Propranolol
Tolbutamide Verapamil
Warfarin
Intermediate: Quinidine
nical Aspect
Clearance Elim. flux/C
Eliminasi dari Unbound Cu (free fraction)
(metabolism, transport) Cu = fuC
)fu biasanya tidak diukur secara rutin(

Hepatic Clearance = EQ
High E (E>0.7), CL sensitive thd Q,
bukan fu Q menurun (Heart
failure, cirrhotic)
Metabolisme menurun
Low E (E<0.3) Q transit time
E
CL sensitive thd fu (CYP induction
 BLOOD OUT
CA CV

D
IN
O
LO
B

Blood Flow = Q

ELIMINATED
Rate of Elimination = QCA QCV = Q(CA-CV)
SIMILARLY FOR
Liver Clearance = Q(CA-CV)/CA = Q x EF OTHER ORGANS

Renal Clearance = UxV/Px

Total Body Clearance = CLliver + CLkidney + CLlungs + CLx

 The principle of linear
pharmacokinetics

Rate of elimin. = CL .
Concentration
 Nonlinear pharmacokinetics
Nonlinear pharmacokinetics: (capacity-
limited, dose or concentration dependent,
saturable)
CL varies depending on the concentration
of a drug.
Rate of elimination = Vmax . C /Michaelis- Menten/
Km + C
CL = Vmax Km + C

ethanol, phenytoin, theofylline

 Total Clearance (CLT or CL)

CL = CLR + CLH + nonrenal/nonhepatic clearance

:Harga CL dari dosis tunggal
Cl i.v. = Dose/AUC 0

: Oral Dose
CL p.o = F. Oral Dose/AUC
F = fraksi dose mencapai central pool
(plasma + jaringan dlm keseimbangan cepat dgn plasma )
 BLOOD OUT
CA
LIVER
CV

D
IN
O
LO
B

Blood Flow = Q

ELIMINATED

Rate of Elimination = QCA QCV = Q(CA-CV)

Hepatic Clearance (Cl h) = Q(CA-CV)/CA=Q x E

Renal clearance
C x Cl r = U x V
C = plasma concentration,
Cl r = renal clearance,
U = urinary concentration,
V = urinary volume
Cl r = U x V/ C
CL t = Kel. Vd
CLt = CLh + Cl r
Renal Clearance )CLR(
.Net Elim. flux = filtration + secretion reabsorb

Net CLR = (urine exc. rate)/(mid-collection C)

)or use 24 hour urine collection and C(t) (

Renal Filtration flux = GFR fuC

GFR CLcreat= 120 ml plasma water/minute
CLR << GFR fu significant reabsorption
CLR >> GFR fu significant secretion