Factors Effecting Metabol and Application of Pharmacokinetics

8/14/2019 Factors Effecting Metabol and Application of Pharmacokinetics

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Pharmacokinetic effects on humanPharmacokinetic effects on human

and fetusand fetus


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PharmacokineticsPharmacokineticsStudy and characterization of the time course of drugStudy and characterization of the time course of drug

absorption, distribution, metabolism and excretion, and theabsorption, distribution, metabolism and excretion, and therelationship of these processes to the intensity and timerelationship of these processes to the intensity and timecourse of therapeutic and toxicology effects of drug.course of therapeutic and toxicology effects of drug.

It describes the processes whereby a drug administered byIt describes the processes whereby a drug administered bya specific mode and in a specific dose is handled by thea specific mode and in a specific dose is handled by the

body, leading to specific drug concentrations in differentbody, leading to specific drug concentrations in differenttissues/organs. Part of drug will reach site(s) of action andtissues/organs. Part of drug will reach site(s) of action andexert its pharmacodynamic action.exert its pharmacodynamic action.

Another way it can be said as what body does to drug.Another way it can be said as what body does to drug.

Pharmacokinetics is used in the clinical setting to enhancePharmacokinetics is used in the clinical setting to enhancethe safe and effective therapeutic management of thethe safe and effective therapeutic management of theindividual patient. This application has been termed asindividual patient. This application has been termed asClinical PharmacokineticsClinical Pharmacokinetics


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The time course of drug concentration in the body after itsThe time course of drug concentration in the body after itsadministration can be defined by a number ofadministration can be defined by a number of

pharmacokinetic parameters.pharmacokinetic parameters.

Information on pharmacokinetics of one drug helps inInformation on pharmacokinetics of one drug helps in

anticipating the pharmacokinetics of anotheranticipating the pharmacokinetics of another The knowledge of pharmacokinetic behavior of one drugThe knowledge of pharmacokinetic behavior of one drug

coupled with important pharmacodynamic parameters likecoupled with important pharmacodynamic parameters like

therapeutic index have several applicationstherapeutic index have several applications

Drug therapy is a dynamic process. When a drug product isDrug therapy is a dynamic process. When a drug product isadministered, absorption continues for a finite period of timeadministered, absorption continues for a finite period of time

and distribution, metabolism, and excretion of drugand distribution, metabolism, and excretion of drug

continues at various rates.continues at various rates.

Pharmacokinetics


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Normally, the aim of a drug therapy is to achieve and maintainNormally, the aim of a drug therapy is to achieve and maintain

effective concentration of drug at the receptor site.effective concentration of drug at the receptor site.

However, as the body constantly tries to eliminate the drug, itHowever, as the body constantly tries to eliminate the drug, it

is necessary to balance absorption against elimination tois necessary to balance absorption against elimination to

maintain the desired concentration.maintain the desired concentration. Often the receptor site are tucked away in a specific organ orOften the receptor site are tucked away in a specific organ or

tissue of the body, i.e., CNS, and it is necessary to depend ontissue of the body, i.e., CNS, and it is necessary to depend on

the blood supply to distribute the drug from the site ofthe blood supply to distribute the drug from the site of

administration, such as GIT, to the site of action.administration, such as GIT, to the site of action.

PharmacokineticsPharmacokinetics


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To achieve the goal by overcoming those processes andTo achieve the goal by overcoming those processes and

barrier, development of proper drug delivery system is mostbarrier, development of proper drug delivery system is most

important.important.

The development of drug delivery system is extremelyThe development of drug delivery system is extremelycomplex and interwoven, and it requires a team approach.complex and interwoven, and it requires a team approach.

Pharmacokinetic and biopharmaceutical aspects are veryPharmacokinetic and biopharmaceutical aspects are very

important in this endeavor.important in this endeavor.

Basic pharmacokinetic understanding of a given drugsBasic pharmacokinetic understanding of a given drugsdisposition in human body is essential for proper design ofdisposition in human body is essential for proper design of

delivery systems.delivery systems.


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Pharmacokinetic principles are being applied byPharmacokinetic principles are being applied by

clinicians to the rational design of dosage regimens.clinicians to the rational design of dosage regimens.

It has become more relevance due to stringentIt has become more relevance due to stringent

regulatory requirements.regulatory requirements.

Pharmaceutical dosage form design, thus, must bePharmaceutical dosage form design, thus, must be

based on a sound knowledge of the pharmacology,based on a sound knowledge of the pharmacology,

physico-chemical properties, pharmacokinetics,physico-chemical properties, pharmacokinetics,pharmacodynamics of the drug and regulatorypharmacodynamics of the drug and regulatory

requirements.requirements.


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Application of PharmacokineticsApplication of PharmacokineticsDesign and Drug Development with greatly improvedDesign and Drug Development with greatly improvedtherapeutic effectiveness and fewer or no toxic effectstherapeutic effectiveness and fewer or no toxic effects

Design and Drug Development of an optimum formulationDesign and Drug Development of an optimum formulationfor better use of the drug.for better use of the drug.

Design and Drug Development of controlled/ targetedDesign and Drug Development of controlled/ targetedrelease formulationrelease formulation

Select appropriate route of drug administrationSelect appropriate route of drug administrationSelect the right drug for a particular illness.Select the right drug for a particular illness.

Predict and explain drug-food and drug-drug interactionsPredict and explain drug-food and drug-drug interactions

Deciding appropriate multiple Dosage RegimenDeciding appropriate multiple Dosage Regimen

Deciding Rational Dose, Frequency And DurationDeciding Rational Dose, Frequency And DurationTherapeutic drug monitoring in individual patientsTherapeutic drug monitoring in individual patients

ADME Study, Bioavailability Or Bioequivalence StudiesADME Study, Bioavailability Or Bioequivalence Studies

Dosage adjustments in situations of altered physiologyDosage adjustments in situations of altered physiologyand drug interactions.and drug interactions.

Pharmacokinetics Pharmacodynamics Relationship.Pharmacokinetics Pharmacodynamics Relationship.


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The applications of pharmacokineticThe applications of pharmacokinetic

principles are mainly aimed at achievingprinciples are mainly aimed at achieving

the therapeutic objective.the therapeutic objective.

It is often control or cure of the condition inIt is often control or cure of the condition in

shortest possible time with minimum sideshortest possible time with minimum side

effects by use of least amount of drug.effects by use of least amount of drug.


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Phamacokinetic ParametersPhamacokinetic Parameters

Overall first order elimination rate constant (K)Overall first order elimination rate constant (K)

Half life ( tHalf life ( t ))Clearance (Total, Renal, Hepatic, etc.) (Cl)Clearance (Total, Renal, Hepatic, etc.) (Cl)

Effective concentration rangeEffective concentration range

Absorption rate constant ( KAbsorption rate constant ( Kaa ))

Extent of bioavailability ( F )Extent of bioavailability ( F )

Fraction of dose excreted unchanged in urine ( XFraction of dose excreted unchanged in urine ( Xuu ))

Blood plasma concentration ratioBlood plasma concentration ratio

Apparent volume of distribution ( VApparent volume of distribution ( Vdd ))

Fraction of protein binding (FFraction of protein binding (Fbb))

Peak concentration (CPeak concentration (Cpp))

Time to reach peak concentration (tTime to reach peak concentration (tpp ))

Toxic concentrationsToxic concentrations


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K3

K-3

Drug at

Absorption site

Drug in

Blood

Drug in Urine

Metabolite(s)

Drug in OtherExcretory Fluids

Drug in Other Fluids of

Distribution

Drug in

Tissues

Ka

K1 K-1 K2 K-2

K4

K5

K6

Schematic representation of drug absorption, distribution, and elimination


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ADME CHARACTERSADME CHARACTERS

AbsorptionAbsorption: Absorption is defined as the process by: Absorption is defined as the process bywhich unchanged proceeds from site of administration towhich unchanged proceeds from site of administration to

site of measurement within the body.site of measurement within the body.

Absorption is not restricted to oral administration. It occursAbsorption is not restricted to oral administration. It occursas well following intramuscular, subcutaneous, and otheras well following intramuscular, subcutaneous, and otherextravascular routes of administration. Monitoring intactextravascular routes of administration. Monitoring intact

drug in blood or plasma offers a useful means ofdrug in blood or plasma offers a useful means ofassessing the entry of drug into the systemic circulation.assessing the entry of drug into the systemic circulation.

There are several possible sites of loss. GI lumen, liver,There are several possible sites of loss. GI lumen, liver,muscle, tissues (sites of administration).muscle, tissues (sites of administration).

The loss as drug passes, for the first time, through sites ofThe loss as drug passes, for the first time, through sites ofelimination, such as the GI membranes and the liver,elimination, such as the GI membranes and the liver,during absorption is termed as first-pass effect.during absorption is termed as first-pass effect.


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DistributionDistribution: The transfer of drug from blood to: The transfer of drug from blood toextravascular fluids (i.e., extra-cellular and intracellularextravascular fluids (i.e., extra-cellular and intracellular

water) and tissues is called distribution. Drug distributionwater) and tissues is called distribution. Drug distribution

is usually a rapid and reversible process.is usually a rapid and reversible process.

Drug in the plasma exists in a distribution equilibrium withDrug in the plasma exists in a distribution equilibrium with

drug in the erythrocytes, in other body fluids and indrug in the erythrocytes, in other body fluids and in

tissues. Changes of plasma drug concentration aretissues. Changes of plasma drug concentration are

indicative of changes in drug level in other tissuesindicative of changes in drug level in other tissues

including sites of pharmacologic effect.including sites of pharmacologic effect.


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Metabolism:Metabolism: It is the biochemical (enzymatic)It is the biochemical (enzymatic)conversion of a drug to another chemical form.conversion of a drug to another chemical form.

Many tissues in the body are capable of metabolizingMany tissues in the body are capable of metabolizingdrugs, but most drugs are mainly metabolized in the liverdrugs, but most drugs are mainly metabolized in the liverby enzymes localized in hepatic microsomes.by enzymes localized in hepatic microsomes.

Drug-metabolizing enzymes oxidize, reduce, hydrolyze,Drug-metabolizing enzymes oxidize, reduce, hydrolyze,

or conjugate compounds. Reduction, oxidation, andor conjugate compounds. Reduction, oxidation, andhydrolytic reactions (phase I pathways) result inhydrolytic reactions (phase I pathways) result inmetabolites with functional groups (hydroxyl, amine, ormetabolites with functional groups (hydroxyl, amine, orcarboxyl) that can be conjugated (phase II).carboxyl) that can be conjugated (phase II).

In man the most common conjugation of drugs orIn man the most common conjugation of drugs ormetabolites occur with acetate, sulfate, glycine, ormetabolites occur with acetate, sulfate, glycine, orglucuronic acid.glucuronic acid.


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EliminationElimination: It is the irreversible loss of drug from the: It is the irreversible loss of drug from thesite of measurement.site of measurement.

The transfer of drug from the blood to the urine or otherThe transfer of drug from the blood to the urine or otherexcretory compartments (i.e., bile, saliva, sweat, milk,excretory compartments (i.e., bile, saliva, sweat, milk,

etc.) and the enzymatic or biochemical transformation ofetc.) and the enzymatic or biochemical transformation ofdrug in the issues or plasma to metabolic products, aredrug in the issues or plasma to metabolic products, areusually irreversible processes. The net result of theseusually irreversible processes. The net result of theseirreversible steps is called drug elimination.irreversible steps is called drug elimination.

Elimination occurs by two processes , excretion andElimination occurs by two processes , excretion andmetabolism. Elimination processes are responsible formetabolism. Elimination processes are responsible forthe physical or biochemical removal of drug from thethe physical or biochemical removal of drug from thebodybody


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ExcretionExcretion: It is the irreversible loss of chemically: It is the irreversible loss of chemicallyunchanged drug by various routes. This can occur throughunchanged drug by various routes. This can occur through

urine, biliary secretion, saliva, sweat, milk, respiratory route.urine, biliary secretion, saliva, sweat, milk, respiratory route.

Routes of excretion and extent of excretion by any routeRoutes of excretion and extent of excretion by any route

may vary from drug to drug depending on nature andmay vary from drug to drug depending on nature and

physicochemical properties of drugs.physicochemical properties of drugs.


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Factors Influence Drug AbsorptionFactors Influence Drug Absorption

Biological FactorsBiological Factors

Physicochemical FactorsPhysicochemical Factors

Formulation FactorsFormulation Factors


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Biological FactorsBiological Factors

Gastrointestinal PhysiologyGastrointestinal Physiology

Anatomy GITAnatomy GIT

Gastrointestinal Blood FlowGastrointestinal Blood Flow

Gastrointestinal pHGastrointestinal pH

Gastric Emptying and Gastrointestinal MotilityGastric Emptying and Gastrointestinal MotilityGIT Contents: acids, enzymes, mucin, bile saltsGIT Contents: acids, enzymes, mucin, bile salts

Effects of Food/Diet on Drug AbsorptionEffects of Food/Diet on Drug Absorption

Presence of other drugsPresence of other drugs

Routes of administrationRoutes of administration


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Physicochemical FactorsPhysicochemical FactorsDrugs pKDrugs pKaa and Gastrointestinal pHand Gastrointestinal pH

Lipid solubility and Partition coefficientLipid solubility and Partition coefficientDissolution and pHDissolution and pH

Diffusion Layer pHDiffusion Layer pH

SaltsSalts

Soluble ProdrugsSoluble Prodrugs

Surface area and particle sizeSurface area and particle size

Crystal formCrystal form

Drugs stability at site of absorptionDrugs stability at site of absorption

ComplexationComplexation

AdsorptionAdsorption

ViscosityViscosity


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Formulation FactorsFormulation Factors

Dosage Forms:Dosage Forms:SolutionsSolutionsSuspensionsSuspensions

CapsulesCapsules

TabletsTablets

Coated TabletsCoated Tablets

Enteric-coated TabletsEnteric-coated Tablets

CR formulationsCR formulations

Targeted or site specific formulaitonsTargeted or site specific formulaitons


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Factors Affecting MetabolismFactors Affecting Metabolism

Genetic VariationGenetic Variation

Environmental DeterminantsEnvironmental Determinants

Inhibition of drug metabolismInhibition of drug metabolism

Induction of drug metabolismInduction of drug metabolism

DiseaseDisease

Age and SexAge and Sex

Body Weight and SizeBody Weight and Size

ObesityObesity

PregnancyPregnancy


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ExcretionExcretion

Drug ExcretionDrug ExcretionRenal ExcretionRenal Excretion

Glomerular filtration, Tubular secretion, TubularGlomerular filtration, Tubular secretion, Tubular

reabsorptionreabsorption

Renal ClearanceRenal ClearanceBiliary ExcretionBiliary Excretion

Salivary ExcretionSalivary Excretion

Secretion of drugs into milkSecretion of drugs into milk

Other excretionOther excretion


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Pharmacokinetic characterization of drugsPharmacokinetic characterization of drugs

for selection of suitable delivery systemsfor selection of suitable delivery systems

compartment modelcompartment model elimination rate constant or terminal half-life(telimination rate constant or terminal half-life(t ))

Area under the concentration-time curve(AUC)Area under the concentration-time curve(AUC)

Total clearance (ClTotal clearance (ClTT))

Apparent volume of distribution (VApparent volume of distribution (Vdd)) Mean steady state concentration (CMean steady state concentration (Cssss ))

Mean residence timeMean residence time

First-pass effectFirst-pass effect

Intrinsic absorption rate constantIntrinsic absorption rate constant

Relative areasRelative areas

Dosage form indexDosage form index


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Important biopharmaceutical characters ofImportant biopharmaceutical characters of

drug for developing delivery systemdrug for developing delivery system

Molecular weightMolecular weight

pKapKa

Isoelectric pointIsoelectric point

SolubilitySolubility

Apparent partition coefficientApparent partition coefficient

Extent of protein bindingExtent of protein binding

Extent ofExtent of1 acid glycoprotein binding1 acid glycoprotein binding

Erythrocyte uptakeErythrocyte uptake

General absorbabilityGeneral absorbability

Biopharmaceutical aspects for route of administrationBiopharmaceutical aspects for route of administration


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Design of Controlled Release formulationDesign of Controlled Release formulation

CCTTis the target concentration to be maintained for T hris the target concentration to be maintained for T hr

Rate of Elimination = K. CRate of Elimination = K. CTT.V.V

ddor 0.693 Cor 0.693 C

TT.V.V

dd

tt1/21/2

Where K is elimination rate constant of the drugWhere K is elimination rate constant of the drugVV

ddis apparent volume of distribution .is apparent volume of distribution .

Rate of absorption, KRate of absorption, Kaa.X.X

aashould be equal to rate ofshould be equal to rate of

elimination to maintain constant concentration. So,elimination to maintain constant concentration. So,KK

aa..

XX

aa= K. C= K. C

TT. V. V

dd

Then rate of release should be equal to rate of absorptionThen rate of release should be equal to rate of absorptionand rate of elimination. Soand rate of elimination. So

rate of release, Krate of release, K rr = K. C= K. CTT.V.Vdd


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So,So,

Maintenance dose = rate of release x duration to beMaintenance dose = rate of release x duration to bemaintainedmaintained

= K. C= K. CTT. V. Vdd.T.T

ttmaxmax == 2.3032.303 LogLog KKaa

KKaa-K K-K K

where Kwhere Kaa is absorption rate constantis absorption rate constant

LoadingdoseLoadingdose == CCTT.V e.V eKtKt maxmax

FFwhere F is bioavailability (fraction)where F is bioavailability (fraction)

P.S: Above is on the basis that drug confers one compartmentP.S: Above is on the basis that drug confers one compartment

distribution.distribution.


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Equation to express plasma concentration of CR productEquation to express plasma concentration of CR product

administeredadministered

C =C =KK

oo(e(e-KT-KT-1)e-1)e-Kt-Kt

VKVK

Where KWhere Koois Zero order release rateis Zero order release rate

T is time of total releaseT is time of total release

t is anytime at which concentration is measured.t is anytime at which concentration is measured.

t can b less than or equal or more than Tt can b less than or equal or more than T

Sit ifi D li


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P-DTOTargetOrgan

DTOTargetOrgan

P-DCCCentralCompartment

DCCCentralCompartment

P-DTCTissueCompa

rtment

DTCTissueCompa

rtment

kLOCAL kLOCAL

k13

k31

k2kinput

k31

k13

kEL

k3k12 k21 k12 k21

P-D Elimination

k1

Scheme 3

Site specific Delivery


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Drug Targeting

(D) +(QC)+ChemicalCoupling

(D-QC)+ Reduction (D-DHC)

(D-DHC)-

BRAIN

Oxidation

(D-QC)+

BRAIN

Enzymatic

cleavage

(D) +(QC)+|BBB

K1

K4

K3

(D-DHC)CIRCULATORY SYSTEM ANDORGANS

Oxidatio

(D-QC)+

CIRCULATORY SYSTEM

K2

(D) +(QC)+|

K3

Elimination

BBB


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Important Considerations

Ideally, drug delivery systems should be designedon the basis of a knowledge of the desired time-

profile of drug response.

It is important to establish the relationship

between in vivo and in vitro profiles (IVIVC) in orderto optimize the formulation and for quality control

purposes.

These objectives require a reliable method for

estimating the rate of bioavailability of the drug fromthe delivery system.


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Pharmacokinetics Evaluation of NovelPharmacokinetics Evaluation of Novel

Delivery Systems in vivo.Delivery Systems in vivo.

The in-vivo evaluation of delivery devices involves two basicThe in-vivo evaluation of delivery devices involves two basicquestionsquestions

Is the desired rate-time profile of release as shown in vitroIs the desired rate-time profile of release as shown in vitroactually obtained in vivo?actually obtained in vivo?

Is the desired response-time profile obtained in-vivo?Is the desired response-time profile obtained in-vivo?

To answer the first, four approaches are thereTo answer the first, four approaches are there

Assay of unreleased drug.Assay of unreleased drug.

Assay of parent drug and/or metabolite in blood, plasma, orAssay of parent drug and/or metabolite in blood, plasma, orserum.serum.

Assay of parent drug and/or metabolite in excretaAssay of parent drug and/or metabolite in excreta

Quantity of response intensity.Quantity of response intensity.


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Second question can be answered if pharmacological orSecond question can be answered if pharmacological or

clinical response can be quantified directly (like bloodclinical response can be quantified directly (like blood

pressure, dilation of pupils, intraocular pressure, urinarypressure, dilation of pupils, intraocular pressure, urinaryoutput, electrolyte excretion, blood glucose levels, etc).output, electrolyte excretion, blood glucose levels, etc).

Otherwise long range clinical studies are required.Otherwise long range clinical studies are required.

The selection or choise of a suitable method for estimatingThe selection or choise of a suitable method for estimatingdrug input rate and pharmacodynamic effect is verydrug input rate and pharmacodynamic effect is very

important.important.


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Pharmacokinetic Consideration of

Site- Specific Drug Delivery Systems

Objective of drug targeting is to deli er a drug to

its site of action and at the same time, minimize any

toxic effects. In pharmacokinetic terms, it aims to

maximize the ratio of drug concentration at its siteof action to that at site of potential toxicity.

The evaluation can be done by:

- Steady state analysis

- Pharmacodynamic aspects

- Temporal aspects

Steady state analysis


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S

R

T

Drug targeting index (DTI)

Steady state analysis

DTI = ------------------

AUCR/AUCT (drug carrier admin.)

AUCR/AUCT (drug admin.)

Qr

Qt

AUCis area under the concentration time profile

armaco ynam c aspec s:


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armaco ynam c aspec s:

AUIT (drug administration)

Target Index, TI = --------

AUIT (drug carrier admins.)

AUI stands for area under the intensity-timeprofile

Temporal aspects: MIR/MIT(drug carrier adm)

MI (Max. Intensity) = --------------

MIR/MIT(drug adm)


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ConclusionConclusion

It is very important to have complete knowledge of pharmacokineticIt is very important to have complete knowledge of pharmacokinetic

characters of drug and factors affecting them to have completecharacters of drug and factors affecting them to have complete

knowledge/study for designing an effective and useful drug delivery systems.knowledge/study for designing an effective and useful drug delivery systems.

Pharmacokinetic study is also important to identify variables that arePharmacokinetic study is also important to identify variables that are

important in determining the potential success of drug delivery systems.important in determining the potential success of drug delivery systems.

It can be used to evaluate the products or delivery systemsIt can be used to evaluate the products or delivery systemsSelection/design of proper experimental protocol is very important. SuitableSelection/design of proper experimental protocol is very important. Suitable

analytical method is necessary for proper estimation.analytical method is necessary for proper estimation.

IV-IV correlation and PK/PD relationship are also useful tool for betterIV-IV correlation and PK/PD relationship are also useful tool for better

design.design.


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Suggested References1. Pharmacokinetics; M.Gibaldi and D. Perrier, Marcel Dekker

Inc.; USA; 2nd edition; 1982.

2. Novel Drug Delivery; Eds. L.F.Prescott and W.S.Nimmo;John Wiley & Sons; UK; 1989.

3. Drug Delivery Devices: Fundamentals and Applications; Ed.

P.Tyle; Marcel Dekker Inc.; USA; 1988.

4. Biopharmaceutics and Clinical Pharmacokinetics; M. Gibaldi;Lee and Febiger; USA, 4th edition; 1991.

5. Modern Pharmaceutics; Eds. G.S.Banker and C.T.Rhodes;

Marcel Dekker Inc.;USA; 3rd edition; 1996.

6. Pharmaceutical Bioequivalence; Eds. P.G.Welling, F.L.S.

Tse and S.V.Dighe; Marcel Dekker Inc.;USA; 1991.

7. Novel Drug Delivery Systems; Ed. Y.W.Chien, Marcel

Dekker Inc.;USA; 2nd edition, 1992


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Factors Effecting Metabol and Application of Pharmacokinetics