INTRODUCTION TO

BIOPHARMACEUTICS AND
PHARMACOKINETICS

OBJECTIVES
To define drug product and biopharmaceutics.
Describe how the principles of biopharmaceutics can affect drug product
performance.
Define pharmacokinetics and describe how pharmacokinetics is related to
pharmacodynamics and drug toxicity.
Define pharmacokinetic model and list the assumptions that are used in
developing a pharmacokinetic model

DRUG PRODUCT PERFORMANCE

The release of the drug substance from the drug
product either for local drug action or for drug
absorption into the plasma for systemic therapeutic
activity.
Safe, more effective and convenient to the patient.

BIOPHARMACEUTICS
Examines the interrelationship of the
physical/chemical properties of the drug, the
dosage form (drug product) in which the drug is
given, and the route of administration on the rate
and extent of systemic absorption.

Absorption

Drug release
and
dissolution

Drug in the
systemic
circulation

Drug in the
tissue

Excretion and
Metabolism

Pharmacologic
or clinical
effect

Elimination

RELATIONSHIP BETWEEN THE DRUG, THE PRODUCT AND PHARMACOLOGIC EFFECT

MINIMUM EFFECTIVE CONCENTRATION

The administered drug reach its site of action

BIOPHARMACEUTICS CONSIDERATIONS IN
PRODUCT DESIGN
ITEMS

CONSIDERATION

THERAPEUTIC OBJECTIVE

Drug is intended for rapid relief of symptoms, slow extended action given once per day (week
or longer), or chronic use, is drug for local or systemic effect.

DRUG

Physical chemical properties of API, including solubility, polymorphic form, particle size.

ROUTE OF
ADMINISTRATION

Oral, topical, parenteral, transdermal, inhalation etc.

DRUG DOSAGE AND

DOSAGE REGIMEN

Large or small drug dose, frequency of doses, patent acceptance of drug product, patient
compliance

TYPE OF DRUG PRODUCT

Orally disintegrating tablets, immediate release tablets, extended release tablets, transdermal,
topical, parenteral, implant, etc.

EXCIPIENTS

Although very little pharmacodynamics activity, excipients affect drug product performance
including release from drug product

METHODS OF
MANUFACTURE

Variables in manufacturing process, including weighing, blending, release testing, sterility.

BIOPHARMACEUTIC FACTORS
The design of the drug product
Stability of the drug within the drug product
The manufacture of the drug product
The release of the drug from the drug product
The rate of dissolution/release of the drug at the absorption site
Delivery of drug to the site of action

IN-VITRO AND IN-VIVO METHODS

IN-VITRO are procedures employing test apparatus and
equipment without involving laboratory animals or humans.
IN-VIVO are more complex studies involving human subjects
and laboratory animals.
Assess the impact of the physical and chemical properties of
the drug, drug stability and large scale production of the drug
and drug product for biological performance of the drug.

PHARMACOKINETICS
Is the science of the kinetics of the drug ADME.

DISPOSITION DME or DEl

Important prerequisite for determination or modification of dosing
regimens for individuals and group patients.

STATISTICAL METHODS
Used for pharmacokinetic parameter estimation and data
interpretation ultimately for the purpose of designing and
predicting optimal dosing regimens for individuals or groups
of patients.
Determine data error and structural model deviation

CLINICAL PHARMACOKINETICS
Application of pharmacokinetic methods to drug therapy.
Optimized dosing strategies based on the patients disease state and patient specific
considerations.
POPULATION PHARMACOKINETICS study of the pharmacokinetic differences of
drugs in various population groups.
Applied in therapeutic monitoring (optimize efficacy and prevent any adverse
toxicity)
Drug with NTI Monitor the plasma concentration of the patient (theophylline),
monitor specific pharmacodynamics endpoint (warfarin PTT).

PRACTICAL FOCUS: RELATIONSHIP OF DRUG

CONCENTRATIONS TO DRUG RESPONSE
TOXIC
POTENTIALLY TOXIC

THERAPEUTIC
POTENTIALLY SUBTHERAPEUTIC
SUBTHERAPEUTIC

PHARMACODYNAMICS
Refers to the relationship between the drug
concentration at the site of action (receptor) and
pharmacologic response (biochemical and physiologic
effects that influence interaction of drug to the
receptor.

DRUG EXPOSURE AND DRUG RESPONSE

DRUG EXPOSURE refers to the dose (drug input into the body) and various measures
of acute or integrated drug concentrations in plasma and other biological fluid (Cmax,
Cmin, Css, AUC)
DRUG RESPONSE refers to the direct measure of the pharmacologic effect of the
drug.
Clinically remote biomarkers (receptor occupancy),
presumed mechanistic effect (ACE inhibition),
potential accepted surrogate (effects on blood pressure, lipid and cardiac output)
full range of short-term or long-term clinical effects related to either efficacy or safety

TOXICOKINETICS AND CLINICAL TOXICOLOGY

TOXICOKINETICS application of pharmacokinetic principles to the design,
conduct and interpretation of drug safety evaluation studies and validating doserelated exposure in animals.
Aid in the interpretation of toxicologic findings in animals and exploration
resulting to data to humans
CLINICAL TOXICOLOGY - study of the adverse effects of drugs and toxic
substances (poisons) in the body.

MEASUREMENT OF DRUG CONCENTRATIONS

BIOLOGICAL SAMPLES (milk, saliva, plasma and urine)
Chromatographic and mass spectrometric methods are most frequently
employed in drug concentration measurement.
Chromatography separates the drug from other related materials that
may cause assay interference.
Mass spectroscopy allows detection of molecules or molecule fragments
based on their mass to charge ratio.

SAMPLING
INVASIVE sampling blood, spinal fluid, synovial fluid, tissue
biopsy or any biological material that requires parenteral or
surgical intervention in the patient.
NON-INVASIVE sampling of urine, saliva, feces, expired air, or
any biological material that can be obtained w/o parenteral or
surgical intervention.

BLOOD
COMPONENT
WHOLE BLOOD

HOW OBTAINED
Whole blood is generally obtained by
venous puncture and contains an
anticoagulant such as heparin or EDTA

COMPONENTS
Whole blood contains all
cellular and protein elements
of blood

SERUM

Serum is the liquid obtained from whole

Serum does not contain
blood after the blood is allowed to clot and cellular elements, fibrinogen
the clot is removed
or the other clotting factors
from the blood

PLASMA

Plasma is the liquid supernatant obtained

after centrifugation of non clotted blood
that contains an anticoagulant

Plasma is the noncellular

liquid fraction of the whole
blood and contains all the
proteins including albumin

PLASMA CONCENTRATION TIME CURVE

ONSET TIME
DURATION OF ACTION
THERAPEUTIC WINDOW
THERAPEUTIC INDEX
PEAK PLASMA LEVEL
TIME FOR PEAK PLASMA
LEVEL
AREA UNDER THE CURVE

PLASMA DRUG CONCENTRATION CURVES

21

22

THERAPEUTIC DRUG MONITORING

Probability (%)

100

Response
Toxicity

50

10

20

30

Drug Concentration (mg/L)

Relationship between drug concentration and drug effects for hypothetical23drug

THERAPEUTIC CHANGES FOR COMMONLY USED

DRUG
DRUG
Digoxin

Lidocaine
Lithium
Phenobarbital

Phenytoin
Quinidine
Theophylline

RANGE
0.5-2.0 ng/mL
1.5-5.0 mg/L
0.6-1.4 mEq/L
15-40 mg/L
10-20 mg/L
2-5 mg/L
5-15 mg/L
24

PROCESS FOR REACHING DECISIONS WITH

THERAPEUTIC DRUG MONITORING
A diagnosis is made
A drug is selected
Dosage schedule is
designed to reach a
target plasma concentration

A drug is administered
Patient assessments
are performed

Drug concentrations
are determined

A pharmacokinetic model is applied

and clinical judgment is used

25

SAMPLE PLOTTING USING SEMILOG AND LINEAR

GRAPHING PAPER

PLOT THE TIME VS. PLASMA DRUG LEVEL

in page
24, 25
Label the points
Use red ball pen for the line and label

 DRUG CONCENTRATIONS IN
TISSUES (biopsy)
URINE (rate and extent of systemic absorption) AND FECES
(mass balance entire dose given to the patient)
SALIVA (pKa of the drug and pH of the saliva)
FORENSIC DRUG MEASUREMENTS (autopsy - abuse)

Order of Reaction
Is the way in which the concentration of a drug or reactant
in a chemical reaction affects the rate
Classes:

Zero-order rate process

First-order rate process
Pseudo-order rate process

28

Significance of Rate Constants

Characterize the change of drug concentration in a
particular reference region
Give the speed at which a drug:
Enters the compartment (absorption rate constant, ka)
Distributes between a central and peripheral compartments (distribution rate
constant)
Is eliminated from the systemic circulation (elimination rate constant, k)

29

Zero versus First order elimination

Zero-order

100%

80%

60%

90%

81%

40%

20%

First-order

100%

72%

64%

30

FIRST ORDER

ZERO ORDER

LINEAR SCALE
It will have a curve line
SEMI LOG
It will have a straight line

LINEAR SCALE
It will have a
straight line
SEMI LOG
It will have a
curve line
31

F
I
R
S
T
O
R
D
E
R
Z
E
R
O

O
R
D
E
R

Time after Drug

Administration
(hours

Amount of drug in
the body (mg)

Amount of Drug
eliminated
Over preceding
hour (mg)

Fraction of Drug
Eliminated over
preceding hour

0
1
2
3
4
5
6

1000
850
723
614
522
444
377

150
127
109
92
78
67

0.15
0.15
0.15
0.15
0.15
0.15

Time after Drug

Administration
(hours

Amount of drug in
the body (mg)

Amount of Drug
eliminated
Over preceding
hour (mg)

Fraction of Drug
Eliminated over
preceding hour

0
1
2
3
4
5

1000
850
700
550
400
250

150
150
150
150
150

0.15
0.18
0.21
0.27
0.38

32

BASIC PHARMACOKINETICS AND

PHARMACOKINETICS MODEL
MODEL a hypothesis using mathematical terms to describe
quantitative relationships concisely.
PHARMACOKINETIC PARAMETER is a constant for the drug that is
estimated from the experimental data. (k depends on tissue sampling,
timing of the sample, drug analysis and predictive model selected.
INDEPENDENT VARIABLE time
DEPENDENT VARIABLE drug concentration

Uses of pharmacokinetic models

Predict plasma, tissue, and urine drug levels with any dosage regimen.
Calculate the optimum dosage regimen for each patient individually.
Estimate the possible accumulation of drugs and/or metabolites.
Correlate drug concentrations with pharmacologic or toxicologic activity.
Evaluate differences in rate or extend of availability between formulations
(bioequivalence).
Describe how changes in physiology or disease affect the absorption, distribution, or
elimination of the drug.
Explain drug interaction.

MODELS
EMPIRICAL MODELS practically but not very useful in explaining the
mechanism of actual process by which drug is absorbed.
PHYSIOLOGICALLY BASED MODELS sample tissue and monitor sample
blood, biopsy, liver tissue.
COMPARTMENT BASED MODELS very simple and useful tool. Describe
this situation is a tank containing a volume of fluid that is rapidly
equilibrated with the drug.

DRUG CONCENTRATION

TISSUES
URINE AND FECES
SALIVA

36

DRUG CONCENTRATION
Drug concentrate in some tissues because of physical
or chemical properties.
Example include digoxin, which concentration in the
myocardium
Lipid soluble drugs (benzodiazepine), concentrate in
the fats.

37

FACTORS CAUSING VARIABILITY IN PLASMA DRUG CONCENTRATION

Difference in individuals ability to metabolize and eliminate

the drug (genetics)
Variations in drug absorption
Disease states or physiologic states (extremes of age) that
alter drug absorption, distribution or elimination
Drug interactions

38

DRUG CONCENTRATION
The amount of drug in a given volume as mg/L;

Amount of drug

Concentration of drug =
Volume in which
Drugs are distributed

39

TIME (hr)

0
0.5
1
2
3
4
5
7

Plasma drug level

(ug/mL)
?
38.9
30.3
18.4
11.1
6.77
4.10
?

40

TWO PARAMETERS OF DRUG

CONCENTRATION
The fluid volume of the tank that will dilute the
drug
The elimination rate of drug per unit of time.

MODEL 1 ONE-COMPARTMENT OPEN

MODEL, IV INJECTION

MODEL 2 ONE-COMPARTMENT OPEN MODEL

WITH FIRST-ORDER ABSORPTION

Ka

MODEL 3 TWO-COMPARTMENT OPEN

MODEL, IV INJECTION
K12

K21

MODEL 4 TWO-COMPARTMENT OPEN

MODEL, WITH FIRST-ORDER ABSORPTION
K12
Ka

K21

CATENARY MODEL MAMMILARY MODEL strongly connected

system, can estimate the amount in any compartment of the system

K12
Ka

1
K21

K23

K32

Model
Is a mathematic description of a biologic system
Is used to express quantitative relations concisely.
A basic type of model used in pharmacokinetics is
compartment models

47

Compartment
Is an entity which can be described by a
definite volume and a concentration
Is a group of tissues with similar blood flow and
drug affinity
Is not a real physiologic or anatomic region
Compartment models are deterministic
because the observed drug concentrations
determine the type of compartmental model
required to describe the pharmacokinetics of
the drug.
48

TYPICAL ORGAN GROUPS FOR CENTRAL AND

PERIPHERAL COMPARTMENTS
Central
Compartment

Examples
Peripheral
Compartment

Heart
Liver

Lungs

Fat
Tissue

Muscle
Tissue

Kidney
Blood

Cerebrospinal
Fluid

NOTE: Central compartment is also known as the highly blood-perfused compartment

Peripheral Compartment is less blood-perfused compartment

49

Complex picture of drug interactions in the body. This gives an

idea of the complexity of drug disposition. Shown are many of the
steps to getting drug from one site in the body to another. Many of
these processes are enzyme induced. Many of these processes
maybe fast or not significant for any given drug.

50

Significance of Compartment
Used to describe and interpret a set of data obtained
by experimentation
Used to characterize with reproducibility the
behavior and the fate of a drug in biological system
when given by a certain route of administration and
in a particular dosage form
Types

One-open compartment
Multiple compartment

Two-open compartment
51

One-open Compartment Model

If the drug entering the body (input)
distributes (equilibrates) instantly between
the blood and other body fluids or tissues
Drug is not necessarily confined to the
circulatory system
Drug may occupy the entire extracellular
fluid, soft tissue or the entire body

52

Distribution occurs instantly

Is not pooled in a specific area
Simpliest
All body tissues and fluids are considered part of
this compartment

53

 Figure shows the body before and after a rapid I.V. bolus injection,

considering the body to behave as a single compartment.

In order to simplify the mathematics it is often possible to assume that a
drug given by rapid intravenous injection, a bolus, is rapidly mixed.
This represents the uniformly mixed drug very shortly after
administration.

54

ONE COMPARTMENT MODEL

K

X0

X1

Where:
X0 = Dose of the drug
X1 = Amount of drug in body
K = Elimination rate constant
55

 Figure shows an intravenous bolus injection with a two

compartment model. Often a one compartment model is not

sufficient to represent the pharmacokinetics of a drug.
A two compartment model often has wider application. Here we
consider the body is a central compartment with rapid mixing and
a peripheral compartment with slower distribution.
The central compartment is uniformly mixed very shortly after
drug administration, whereas it takes some time for the peripheral
compartment to reach a pseudo equilibrium.
56

TWO-COMPARTMENT MODEL
Where:
X0 = Dose of the drug
X1 = Amount of drug in the
X0
central compartment
X2 = Amount of drug in the peripheral
compartment
K = Elimination rate constant of drug
from the central compartment to the
outside of the body
K12 = Elimination rate constant of drug
from the central compartment to the
peripheral compartment
K21 = Elimination rate constant of drug
from the peripheral compartment to
the central compartment

X1
K12

K
K21

X2

57

COMPARTMENT MODEL REPRESENTING

TRANSFER OF DRUG FROM CENTRAL AND
PERIPHERAL COMPARTMENTS
Intravenous
Administration

Elimination

Central

PERIPHERAL
58

DRUG CONCENTRATION
The amount of drug in a given volume as mg/L;

Amount of drug

Concentration of drug =
Volume in which
Drugs are distributed

59

VOLUME OF (V) or (Vd)

Is an important indicator of the extent of drug distribution
into the body fluids and tissue.
V relates the amount of drug in the body (X) to the measured
concentration in the plasma (C)
V is the volume required to account for all the drug in the
body if the concentrations in all tissues are the same as the
plasma concentration.

X = VC

V=X
C

C=X
V
Amount of drug

Volume of distribution =
Concentration
60

LARGE vs. SMALL

VOLUME OF DISTRIBUTION

A large volume of distribution

usually indicates that the drug
distributes Extensively into body
tissues and fluids.
Small volume of distribution often
indicates limited drug distribution
61

USES OF VOLUME OF DISTRIBUTION

Indicates the extent of distribution but not
the tissues or fluids in which the drug is
distributing.
Two drugs can have the same Vd but differ
on the concentration site (muscles tissues,
adipose tissues)
The smallest volume in which a drug may
distribute is the plasma volume/.
62

APPROXIMATE VOLUMES OF DISTRIBUTION COMMONLY USED DRUGS

DRUG
Nortriptyline
Digoxin
Propranolol
Lidocaine
Phenytoin
Theophylline
Gentamicin

Volume of distribution
1300
440
270
77
45
35
18
63

SAMPLE PROBLEMS
If 100 mg of drug X is administered IV and the plasma
concentration is determines to be 5 mg/L just after the dose
is given. What is the volume of distribution?
If the first 80-mg dose of Gentamicin is administered IV and
results in a peak plasma concentration of 8 mg/L, What
would be the volume of distribution?

64

TIME COURSE PLASMA GENTAMICIN

CONCENTRATION

Concentration
(mg/L)

Time after
Dose (hours)

6
4.4
2.4
0.73

1
2
4
8
65

CLINICAL CORRELATE
Drugs that have
extensive distribution
outside of the plasma
appear to have a large
volume of distribution.

Examples
Chloroquine
Digoxin
Diltiazem

Dirithromycin
Imipramine
Labetalol
Metoprolol
Meperidine
Nortriptyline
66

PLASMA DRUG CONCENTRATION

The prediction of plasma
concentrations is based on
known concentrations.

67

PLASMA DRUG CONCENTRATION CURVES

68

69

QUESTIONS:
If a 3 g of a drug are added and
distributed through out a tank and the
resulting concentration is 0.15 g/L,
calculate the volume of the tank.
A. 10 L
E. 10 g/L
B. 20 L
F. 20 g/L
C. 30 L
G. 30 g/L
D. 200 L
H. 200 g/L
70

2. A drug follows a one-compartment model is given as an

IV injection, and following plasma concentartions are
determined at the times indicated
Plasma Concentration (mg/L)

Time after Dose (hours)

81
67
55

1
2
3

Using semilog graph paper, determine the approximate

concentration in plasma at 6 hours after the dose.
A. 18 mg/L
B. 30 mg/L
C. < 1 mg/L

71

BASIC PHARMACOKINETICS
To examine the concept of volume of distribution (V or Vd).
One way is to compute apparent volume of distribution in
the body.
Apparent volume of distribution in the body is determined
by measuring the plasma concentration immediately after
administration before elimination has had a significant
effect.
The concentration just after IV administration (at time zero)
is abbreviated as C0. The volume of distribution can be
calculated using the equation:
Amount of drug
Xo (mg
Vd = administered dose or Vd = -----------Initial Drug Concentration
Co (mg/L)
72

Measurement of Co
Co can be measured from direct measurement or
estimation by back-extrapolation from concentrations
determined at any time after the dose.
It is done by extending to the y-axis
The point where that line crosses the y-axis gives an
estimate of Co.

73

FLUID DISTRIBUTION IN ADULT

The fluid portion (water) in an adult makes approximately 60% of the total body
weight and is composed of:
35 % intracellular fluid
25 % extracellular fluid
Plasma (4%)
Interstitial fluid (21%)
BLOOD refers to the fluid portion in combination with formed elements (WBC, RBC and
Platelets)
PLASMA refers only to the fluid portion of the blood (including soluble proteins but nor
formed elements)
SERUM When the soluble protein fibrinogen is removed in the plasma

74

EXERCISE:
A dose of 1000 mg of a drug is
Plasma
Time after
administered to a patient, and the
Concentration Dose (hours)
following concentration results at the
(mg/L)
indicated times below. Assume a one100
2
compartment model.
67
4
45
6

An estimate of the volume of distribution would be:

A. 10.0 L.
B. 22.2 L
C. 6.7 L
D. 5.0 L
75

EXERCISE
Time after dose
(hours)
2
4
6

Plasma Concentratiom
(mg/L)
15
9.5
6

1. The plasma concentration at 9 hours after.

2. An estimate for the apparent volume of
distribution of a 1000 mg dose
76

CLEARANCE
Clearance is a measure of a removal of drug from the
body.
Plasma drug concentrations are affected by the rate at
which the drug is administered, the volume by which it
distributes, and its clearance.
A drug clearance and its volume of distribution
determine its half-life.
Clearance (expressed as volume/time) describes the
removal of a drug from a volume of plasma in a given
period of time (drug loss from the body)
77

CLEARANCE
Clearance does not indicate the amount of
drug being removed.
It indicates the volume of plasma (or
blood) from which the drug completely
removed, or cleared, in a given time
period.

78

AREA UNDER THE CURVE

The area under the plasma drug concentrationtime curve (AUC) reflects the actual body
exposure to drug after administration of a dose
of the drug and is expressed in mg*h/L.

79

This area under the curve is dependent on the rate of

elimination of the drug from the body and the dose
administered.
The total amount of drug eliminated by the body may
be assessed by adding up or integrating the amounts
eliminated in each time interval, from time zero
(time of the administration of the drug) to infinite
time.
This total amount corresponds to the fraction of the
dose administered that reaches the systemic
circulation.
80

AUC AREA UNDER THE CURVE or area under the

plasma concentration
AREA METHOD
AUC =

dose administered
AUC = (C1+C0)(t2-t1) + (C2+C1)(t3-t2) etc
drug clearance
2
2
Drug clearance = dose administered (X0)
AUC
AUC or terminal area = Clast
AUC = initial concentration (Co)
K
elimination rate constant (K)

81

AREA UNDER THE CURVE

Computing the plasma concentration of 10 get the Cp at time 0 and 10 hours, then compute for the K.
K = ln Clast-lnC0 / t0 -tlast

K = 0.2589 hr-1
;
Cp10 = 0.29 mg/L / 0.2589 hr-1 = 1.12 (mg/L) x hr

Time after the dose (hours)

0
0.5
1.0
2.0
3.0
5.0
7.0
10.0
10.0

AUC0.50
AUC10.5
AUC21
AUC32
AUC53
AUC75
AUC107
= Clast
K

Plasma Drug Concentration (mg/L)

3.86
3.36
3.00
2.29
1.77
1.06
0.63
0.29
?
TOTAL

1.81 (mg/L) x hr
1.59 (mg/L) x hr
2.65 (mg/L) x hr
2.03 (mg/L) x hr

2.83 (mg/L) x hr
1.69 (mg/L) x hr
1.38 (mg/L) x hr
1.12 (mg/L) x hr
15.10 (mg/L) x hr

The following drug concentration and time data were obtained after an IV bolus dose of
procainamide (420 mg) Calculate the clearance by area method. Cl = X0 / AUC
82
Cl = 420 mg / 15.10 (mg/L) x hr = 27.81 L/hr.

Computing the plasma concentration of 10 get the Cp at time 0 and 10 hours, then compute for the K.
K = ln Clast-lnC0 / t0 -tlast

K = 0.2589 hr-1 ;
Cp10- = 0.29 mg/L / 0.2589 hr-1 = 1.12 (mg/L) x hr

(3.86 + 3.36) (0.5-0)

2
AUC0.50

AUC10.5

AUC21
AUC32
AUC53
AUC75

AUC107

1.81 (mg/L) x hr
1.59 (mg/L) x hr
2.65 (mg/L) x hr
2.03 (mg/L) x hr
2.83 (mg/L) x hr
1.69 (mg/L) x hr
1.38 (mg/L) x hr
1.12 (mg/L) x hr

AUC 0-t= 13.98 mg/L . hr

AUC t- = Clast/K =

= 0.29/0.2589

= 1.12 mg/L . hr
AUC 0- = 13.98 mg/L.hr +

1.12 mg/L . hr

= 15.10 mg/L . hr

Clearance
Drugs can be cleared from the body by many different
mechanism, pathways, or organs, including hepatic
biotransformation and renal and biliary excretion.
Total body clearance of drug is the sum of all the clearances
by various mechanisms.

84

CLEARANCE
Clt = Clr + Clm + Clb + Clother
Where
Clt = total body clearance (from all mechanisms, where t refers to total
Clrn = renal clearance (through renal excretion)
Clm = clearance by liver metabolism or biotransformation
Clb = biliary clearance (through biliary excretion); and
Clother = clearance by all other routes (gastrointestinal tract, pulmonary,
etc.)

85

Model for Organ Clearance of a Drug

For agent removed primarily by the kidneys, renal
clearance (Clr) makes up most of the total body
clearance.
For drug primarily metabolized by the liver, hepatic
clearance (Clm) is most important.
Cin

Organ of
Elimination
(Liver, Kidney)

Cout
Q

Elimination
(urine or bile)
86

 Where Q (mL/min) is the blood flow through the

organ
Cin is the drug concentration in the blood entering
the organ
Cout is the drug concentration in the exiting blood.
If the organ eliminations some of the drug, Cin is
greater than Cout.
Cin

Organ of
Elimination
(Liver, Kidney)

Cout
Q

Elimination
(urine or bile)
87

E = extraction ratio
We can measure an organs ability to remove a drug by relating
Cin and Cout. This extraction ration is
E = Cin Cout
Cin

Extraction Ratio (E)

Rating

>0.7
0.3-0.7
< 0.3

High
Intermediate
Low
88

EXTRACTION RATIO
Must be fraction between zero and one.
Organs that are efficient at eliminating a drug will have an extraction
ratio approaching one
Clearance of any organ is determined by blood flow and the
extraction ratio.
Organ clearance = blood flow x extraction ratio
or Clorgan = Q x Cin - Cout
Cin

or Clorgan = QE
89

Example:
The amount of drug in the body is 850 mg and150 mg was eliminated via the
bile. The blood flow is 20 mL/min. What would be the clearance in the bile?
Cl bile = (850-150) / 850 = 0.82 x 20 mL/min = 16.40 mL/min
The amount of drug in the body is 780 mg and 100 mg was eliminated via
the lungs. The blood flow is 15 mL/min. What would be the clearance in the
lungs?
Cl lungs = (780-100) / 780 = 0.87 x 15 mL/min = 13.05 mL/min
The amount of drug in the body is 670 mg and 130 mg was eliminated via
the liver. The blood flow is 38 mL/min. What would be the clearance in the
liver?
Cl liver = (670-130) / 670 = 0.81 x 38 mL/min = 30.78 mL/min
The amount of drug in the body is 550 mg and 160 mg was eliminated in the
kidney. The blood flow is 46 mL/min. What would be the clearance in the
kidney?
(550-160) / 550 = 0.71 x 46 mL/min = 32.66 mL/min
Compute for the total body clearance.
C total = 16.40 + 13.05 + 30.78 + 32.66 = 92.89 mL/min
90

Effect of Clearance
Extraction ratio
(E)

High (0.7-1.0)
Low (<0.3)
High (0.7-1.0)
Low (<0.3)

Blood flow (Q) Clearance (Cl)

(L/hour)
(L/hour)

Low
High
High
Low

Low
Low
High
Low

91

AVERAGE CLEARANCES AMONG COMMON DRUGS

DRUG

CLERANCE

Aspirin
Cephalexin
Digoxin
Gentamicin
Lovastatin
Ranitidine
Vancomycin
Zidovudine

650 mL/min.
300 mL/min.
130 mL/min.
90 mL/min.
4-18 mL/min.
730 mL/min.
98 mL/min.
26 mL/min.
92