BIO-AVAILABILITY

PRESENTED BY PREMSAI.KI M PHARMPHARMACEUTICSKRUPANDHI COLLEGE OF PHARMACY BANGALORE

CONTENT

Definition Purpose of bio availability Factors affecting bio availability Measurements of bio availability Reasons for poor availability Approches to enhance the bio availability Methods of enhancement of bio

availability Reference

BIO BIO AVAILABILITYAVAILABILITY BIO AVAILABILITY means the

rate and extent of drug reaches the systemic circulation in its unchanged form following the administration of a dosage form

PURPOSE OF BIOAVAILABILITYPURPOSE OF BIOAVAILABILITY

For marketing approval of new drug, FDA meets bioavailability studies

Establish the pharmacokinetic characters and it is useful in establish dosage regimens

Bio availability studies are useful in determining the safety, efficacy, identity, strength, quality and purity of the drug product

Factors affecting Bioavailability

A)Pharmaceutic factors :1) Physicochemical properties of drug Drug solubility & dissolution rate. Particle size & effective surface area. Polymorphism & Amorphism. Amorphous > metastable > stable Pseudopolymorphism (Hydrates /

Solvates ) Anhydrates > hydrates e.g.

Theophylline, Ampicillin Organic solvates > non solvates e.g.

fludrocortisone

Salt form of the drug. Weakly acidic drugs – strong basic

salt e.g.barbiturates , sulfonamides. Weakly basic drugs – strong acid salt Lipophilicity of the drug . pKa of the drug & pH . Drug stability.

2) Dosage form characteristics & Pharmaceutic Ingredients Disintegration time (tab/cap) Dissolution time. Manufacturing variables. Pharmaceutic ingredients( excipients /

adjuvants ) Nature & type of dosage form. Solutions> Emulsions> Suspensions>

Cap> Tab> Enteric Coated Tab > Sustained Release

Product age & storage conditions.

B)Patient related factors Age Gastric emptying time . Intestinal transit time . Gastrointestinal pH .(HCL > Acetic > citric ) Disease States . Blood flow through the gastrointestinal tract

. Gastrointestinal contents : Other drugs .

Food . Fluids Other normal g.i. contents Presystemic metabolism (First – Pass

effect ) by : Luminal enzymes . Gut wall enzymes . Bacterial enzymes . Hepatic enzymes .

C)Routes of administration :

Parentral > Rectal > Oral >

Topical

Route Bioavailability (%) characterstics

Intravenous 100 (by definition) Most rapid onset (IV) Intramuscular 75 to ≤ 100 Large volumes often

feasible; (IM) may be

painful

Subcutaneous 75 to ≤ 100 Smaller volumes than IM; may be painful

(SC) Oral (PO) 5 to < 100 Most convenient; first

pass effects may be significant Rectal (PR) 30 to < 100 Less first-pass effects

than oral Inhalation 5 to < 100 Often very rapid

onset

Transdermal 80 to ≤ 100 Usually very slow absorption;

used lack of first-pass effects; prolonged duration of action

MEASUREMENT OF BIO MEASUREMENT OF BIO AVAILABILITYAVAILABILITYDivided in to three categories. Pharmacokinetic method Pharmacodynamic method scientgraphy studySelection of method depends on

the: Purpose of the study Analytical method of drug

measurement Nature of the drug product

PHARMACOKINETIC METHODPHARMACOKINETIC METHOD

It is also called as Indirect method

Plasma level-time studies

Urinary excretion studies

PLASMA LEVEL-TIME STUDIESPLASMA LEVEL-TIME STUDIES

PRINCIPLE:

It is based on the assumption that two dosage forms that exhibit super imposable plasma level time profile in a group of subjects should result in identical therapeutic activity

FOR SINGLE DOSE STUDYFOR SINGLE DOSE STUDY It requires collection of serial blood

samples for a period of 2 to 3 biological half lives, after drug administration

And then analysis for drug concentration

By making a plot of concentration vs corresponding time of sample collection to obtain plasma level time profile

FOR MULTIPLE DOSEFOR MULTIPLE DOSE

Method involves drug administration for at least 5 biological half lives

A blood sample should be taken at the end of previous dosing interval and 8 to 10 samples after the administration of next dose

PARAMETERSPARAMETERS3 parameters of these method

used to estimate the bio availability are:

Cmax : Peak plasma concentration.

Tmax : Peak time AUC : Area under the plasma

level- time curve

Time

tmax

CMAXPLASMA CONC

PLASMA DRUG LEVEL-TIME CURVE

MEASUREMENT OF AUCMEASUREMENT OF AUC 1)PHYSICAL METHODS

A)CUT AND WEIGHT METHOD B)PLANIMETER

2)TRAPEZOIDAL METHOD

3)INTEGRATION METHOD

RELATIONSHIP BETWEEN AUC AND DOSE

AUC

Dose

AUC

Dose

CUT & WEIGH AND CUT & WEIGH AND PLANIMETER METHODSPLANIMETER METHODS

CUT & WEIGH: Plasma concentration profile are plotted on smooth paper, these can be cut out and weighed and the weight of the papers is directly proportional to AUC

PLANIMETER : A planimeter is a percision instrument which allows the calculation of areas by tracing there outlines

TRPEZOIDAL METHODTRPEZOIDAL METHOD

It involves the breaking up of the plasma con vs time profile in to several trapezoids calculating the area of each trapezoid and add them to obtain the AUC

AUC = [(co+c1)(t1-to)/2]+……… +

(cn-1+cn)(tn-tn-1)/2

INTEGRATION METHODINTEGRATION METHOD

AUC=A(1/Ke-1/Ka)

where Ke=overall elimination

constant Ka=absorption constant

EXTENT OF EXTENT OF BIOAVAILABILITY FOR BIOAVAILABILITY FOR SINGLE DOSE STUDYSINGLE DOSE STUDYF=[AUC]oral Div / [AUC]iv Doral

Fr=[AUC]testDstd/[AUC]stdDtest

D = DOSE

ADMINISTERED

EXTENT OF BIOAVAILABILITY EXTENT OF BIOAVAILABILITY FOR MULTIPLE DOSE STUDYFOR MULTIPLE DOSE STUDYFr=[AUC]testDstdTtest/[AUC]stdDtestTstd

T=Dosing interval Bioavailability can also be measured

by peak plasma concentration at steady state,

Fr=[Cssmax]testDstdTtest/[Cssmax]stdDtestTstd

T=dosing interval

URINARY EXTRECTION STUDIESURINARY EXTRECTION STUDIES PRINCIPLE : It involves urinary

excretion of unchanged drug is directly proportional toplasma concentration of drug

Eg : thiazide diuretics, sulphonamides

For drugs that have urine as site of

action eg: urinary antiseptics :

nitrofurantoin.

METHOD FOR URINARY METHOD FOR URINARY EXCRETION STUDIESEXCRETION STUDIES It involves collection of urine at

regular intervals for a time span equal to 7 biological half lives

Then analysis for unchanged drug in the collected sample

Then determined the amount of drug excreted in each interval and cumulative amount excreted

PARAMETERS

(dxu/dt)max: Max urinary excretion rate.

(Tu)max: Time for Max excretion rate.

(Xu):Cumulative amount of drug excreted in the urine

E

X

CR

E

T

I

ON

URINE COLLECTION PERIOD

((dxu/dt)maxdxu/dt)max

(Tu)max(Tu)max

URINARY EXCRETION URINARY EXCRETION STUDIESSTUDIES

EXTENT OF BIOAVAILABILITY FOR SINGLE DOSE

F=(Xu)oralDiv/(Xu)ivDoral

Fr=(Xu)testDstd/(Xu)Dstd

EXTENT OF BIOAVAILABILITY FOR MULTIPLE DOSE STUDY AT STEADY STATEFr=(Xu,ss)testDstdTtest/

(Xu,ss)stdDtestTstd

(Xu,ss) It is the amount of drug excreted in unchanged form during a single dosing interval at Steadystate

ADVATAGES OF URINARY EXCRETION STUDIES

These method is useful when there is a lack of sufficiently sensitive analytic tech to measure concentration of drugs in plasma with accuracy

Convenince of collecting urine samples. Direct measurement of absolute and

relative bioavailablity is possible without the neccesity of fitting the data to a mathematic model

When coupled with plasma level-time data,it can be used to estimate renal clearance of un changed drug,by

CLR=total amount of drug excreted unchanged / AUC

PHARMACODYNAMIC METHOD

It is also called as direct method

Acute pharmacological response

Therapeutic response

ACUTE PHARMACOLOGICAL RESPONSE Acute pharmacological effect such as change in ECG OR EEG readings,pupil diameter etc is related to the time course of a given drug

Bioavailability can be determined: By construction of

pharmacologic effect - time curve By dose-response graphs

THERAPEUTIC RESPONSE

This method is based on observing the clinical response to a drug formulation given to a patient suffering from disease for which it is intended to be used

Draw back is difficult assessment of relative bio availability between two dosage forms of the same drug

SCIENTGRAPHY STUDY

Radioactive substances is used to investigate the extent of absorption of drugs, which are directly introduced to the colon or targeted to colon

REASONS FOR POOR BIO-AVAILABILITY

Poor aqueous solubility or slow dissolution rate.

Poor stability of the dissolved drug at the physiologic PH

Inadequate partition coefficient and thus poor permeation through the bio membrane.

Extensive pre-systemic metabolism.

APPROACHES TO ENHANCE THE BIOAVAILABILITY

THE PHARMACEUTIC APPROACH

THE PHARMACOKINETIC APPROACH

THE BIOLOGIC APPROACH

METHODS FOR ENHANCEMENT OF BIOAVAILABILITY

MICRONIZATION: Steroidal drugs, sulfa drugs, griseofulvin

USE OF SURFACTANTS: Polysorbates increases the bio avaialability of spiranolactone

USE OF SALT FORMS : Alkali metal salts of acidic drugs like pencillin, strong acid salts of basic drugs like atropine have more water soluble than parent drug

ALTERATION OF PH OF ALTERATION OF PH OF MICROENVIRONM ENT OF DRUG:MICROENVIRONM ENT OF DRUG: by two by two waysways A) In situ salt formation B) A) In situ salt formation B) addition of buffers eg: buffered aspirin addition of buffers eg: buffered aspirin tabletstabletsUSE OF META STABLE POLYMORPHSUSE OF META STABLE POLYMORPHS: : Eg: B- chloramphenicol palmitate is Eg: B- chloramphenicol palmitate is more water soluble than A and Cmore water soluble than A and C

SELECTIVE ADSORPTION ON INSOLUBLE SELECTIVE ADSORPTION ON INSOLUBLE CARRIERSCARRIERS : Bentonite can enhance the : Bentonite can enhance the dissolution of poorly water soluble dissolution of poorly water soluble drugs such as indometacin,prednisone drugs such as indometacin,prednisone by twoby two reasons weak physical bonding reasons weak physical bonding between adsorbate and adsorbent and between adsorbate and adsorbent and hydration, sweeling of clay in aqueous hydration, sweeling of clay in aqueous mediamedia

SOLID SOLUTIONS: a) use of solid solutions b)use of eutectic mixtures

c)use of solid dispersions

reduces the particle size by different mechanisms and thus enhances the bioavailability.

MOLECULAR ENCAPSULATION WITH CYCLODEXTRIN : the beta dextrins and there derivatives have ability to molecular inclusion complexes with hydro phobic drugs having poor water solubility.the out side of the host molecule have water soluble and thus improves the aqueous solubility and dissolution rate and thus bio availability. Eg: thiazides diuretics

REFERENCES

1. D.M. Brahmankar, Biopharmaceutics and Pharmacokinetics, Vallabh prakashan, second editon, 2009

2. Shagel Wu-pong yu, bio pharmaceutics &pharmacokinetics, fifth edition ,2005

3. www. Goggle.com 4. en.wikipedia.org 5. Amidd.inon,g.l,Lennernas, A therotical basis

for a biopharmaceutical drug classification WWW.pubmed