Chapter 1 Introduction to Biopharmaceutics and Pharmacokinetics 1

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.

Drug release and

dissolution

Drug in the systemic

circulation

Excretion and Metabolism

Drug in the tissue

Pharmacologic or clinical

effect

Absorption

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 dose-related 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

HOW OBTAINED COMPONENTS

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

Whole blood contains all cellular and protein elements of blood

SERUM Serum is the liquid obtained from whole blood after the blood is allowed to clot and the clot is removed

Serum does not contain cellular elements, fibrinogen 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 noncellularliquid 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

THERAPEUTIC DRUG MONITORING

23

Pro

babili

ty (

%)

Drug Concentration (mg/L)

Toxicity

Response

0 10 20 30

50

100

Relationship between drug concentration and drug effects for hypothetical drug

THERAPEUTIC CHANGES FOR COMMONLY USED DRUG

DRUG RANGE

Digoxin

Lidocaine

Lithium

Phenobarbital

Phenytoin

Quinidine

Theophylline

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/L24

25

A diagnosis is made

A drug is selected

Dosage schedule is

designed to reach a

target plasma concentration

A drug is administered

Drug concentrations

are determined

Patient assessments

are performed

A pharmacokinetic model is applied

and clinical judgment is used

PROCESS FOR REACHING DECISIONS WITH

THERAPEUTIC DRUG MONITORING

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 processFirst-order rate processPseudo-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

30

Zero-order

First-order

100%

100%

80% 60% 40% 20%

90% 81% 72% 64%

FIRST ORDER ZERO ORDER

LINEAR SCALE

It will have a curve line

SEMI LOG

It will have a straight line

31

LINEAR SCALE

It will have a

straight line

SEMI LOG

It will have a

curve line

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

0.3832

F

I

R

S

T

O

R

D

E

R

Z

E

R

O

O

R

D

E

R

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;

39

Concentration of drug =

Amount of drug

Volume in which

Drugs are distributed

TIME (hr) Plasma drug level (ug/mL)

0 ?

0.5 38.9

1 30.3

2 18.4

3 11.1

4 6.77

5 4.10

7 ?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

1 K

MODEL 2 ONE-COMPARTMENT OPEN MODEL WITH FIRST-ORDER ABSORPTION

1 KKa

MODEL 3 TWO-COMPARTMENT OPEN MODEL, IV INJECTION

1

K

K12

K212

MODEL 4 TWO-COMPARTMENT OPEN MODEL, WITH FIRST-ORDER ABSORPTION

1

K

K12

K212Ka

CATENARY MODEL MAMMILARY MODEL strongly connected system, can estimate the amount in any compartment of the system

1

K12

K21

2KaK23

K32

3

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 deterministicbecause 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

49

Central

Compartment

Heart

Liver

Lungs

Kidney

Blood

Examples

Peripheral

Compartment

Fat

Tissue

Muscle

Tissue

Cerebrospinal

Fluid

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

Peripheral Compartment is less blood-perfused compartment

50

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.

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

54

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.

ONE COMPARTMENT MODEL

55

X0 X1

K

Where:

X0 = Dose of the drug

X1 = Amount of drug in body

K = Elimination rate constant

56

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.

TWO-COMPARTMENT MODEL

Where:

X0 = Dose of the drug

X1 = Amount of drug in the

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

57

X1 KX0

X2

K12 K21

58

Intravenous

Administration

Central

PERIPHERAL

Elimination

COMPARTMENT MODEL REPRESENTING

TRANSFER OF DRUG FROM CENTRAL AND

PERIPHERAL COMPARTMENTS

DRUG CONCENTRATION

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

59

Concentration of drug =

Amount of drug

Volume in which

Drugs are distributed

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.

60

Volume of distribution =

Amount of drug

Concentration

X = VC C = X

VV = X

C

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 Volume of distribution

Nortriptyline

Digoxin

Propranolol

Lidocaine

Phenytoin

Theophylline

Gentamicin

1300

440

270

77

45

35

1863

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

865

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

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/LB. 20 L F. 20 g/LC. 30 L G. 30 g/LD. 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

71

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

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:

72

Amount of drug Xo (mg

Vd = administered dose or Vd = ------------

Initial Drug Concentration Co (mg/L)

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 administered to a patient, and the following concentration results at the indicated times below. Assume a one-compartment model.

Plasma

Concentration

(mg/L)

Time after

Dose (hours)

100

67

45

2

4

6

75

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

EXERCISE

Time after dose

(hours)

Plasma Concentratiom

(mg/L)

2

4

6

15

9.5

6

76

1. The plasma concentration at 9 hours after.

2. An estimate for the apparent volume of

distribution of a 1000 mg dose

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


The area under the plasma drug concentration-time 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

AUC = dose administered

drug clearance

Drug clearance = dose administered (X0)

AUC

AUC = initial concentration (Co)

elimination rate constant (K)

AREA METHOD

AUC = (C1+C0)(t2-t1) + (C2+C1)(t3-t2) etc

2 2

AUC or terminal area = ClastK

81


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

Cl = 420 mg / 15.10 (mg/L) x hr = 27.81 L/hr.

Time after the dose (hours) Plasma Drug Concentration (mg/L)

0

0.5

1.0

2.0

3.0

5.0

7.0

10.0

10.0 = Clast

K

3.86

3.36

3.00

2.29

1.77

1.06

0.63

0.29

?

TOTAL

82

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

AUC0.50

AUC10.5AUC21AUC32AUC53

AUC75AUC107

1.81 (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

1.59 (mg/L) x hr

15.10 (mg/L) x 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 -tlastK = 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

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

AUC0.50

AUC10.5

AUC21

AUC32

AUC53

AUC75

AUC107

1.81 (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

1.59 (mg/L) x 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 + ClotherWhere

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.

86

Organ of

Elimination

(Liver, Kidney)Q

CinCout

Q

Elimination

(urine or bile)

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.

87

Organ of

Elimination

(Liver, Kidney)Q

CinCout

Q

Elimination

(urine or bile)

E = extraction ratio

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

E = Cin CoutCin

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 xCin - 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

91

Extraction ratio

(E)

Blood flow (Q)

(L/hour)

Clearance (Cl)

(L/hour)

High (0.7-1.0)

Low (

AVERAGE CLEARANCES AMONG COMMON DRUGS

DRUG

Aspirin

Cephalexin

Digoxin

Gentamicin

Lovastatin

Ranitidine

Vancomycin

Zidovudine

CLERANCE

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

Chapter 1 Introduction to Biopharmaceutics and Pharmacokinetics 1

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