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Chapter 1 Introduction to Biopharmaceutics and Pharmacokinetics 1

Nov 02, 2015

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Marc Alamo

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
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  • 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

  • 22

  • 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

  • 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/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

  • AREA UNDER THE CURVE

    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

  • AREA UNDER THE CURVE

    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.

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    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

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  • 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

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  • 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

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  • 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