SEMINAR- Bioavailability

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SEMINAR BIOAVAILABILITY Dr. Mayur M. Maybhate JR-1, Dept. of Pharmacology IGGMC, Nagpur.

Introduction and History:

Introduction and History Phenytoin tragedy – Inert diluent Calcium sulphate was substituted by Lactose.


Definition Rate and extent of drug from a dosage form or the fraction of drug that reaches the site of action.

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Rate and extent of therapeutic moiety in form of parent drug; active metabolite; or active moiety of prodrug from administered dosage form appearing in systemic circulation.

Calculation of Bioavailability:

Calculation of Bioavailability

Terminologies in Bioavailability:

Terminologies in Bioavailability Absolute Bioavailability Denoted by ‘F’. Ranges from 0-1. Expressed as µg-hr/ml. F = AUC ev/AUC iv

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Route Bioavailability Remark 1) Intravenous 100% Most rapid 2) Intramuscular 75-100% Large volumes needed, Painful 3) Subcutaneous 75-100% Smaller volumes than IM, Often painful 4) Oral 5- < 100% Most convenient, First pass effect significant 5) Rectal 30- < 100% Less first pass effect than oral 6) Inhalational 5- < 100% Very rapid onset 7) Transdermal 80-100% Slow onset

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Relative Bioavailability Bioavailability of a drug product as compared to another dosage form or products of same drug given in same dose. F = AUC a/ AUC b

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Bioequivalence Two drug products are said to be equivalent if rate and extent of their bioavailability is not significantly different under similar test conditions.

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Clinical Equivalence Therapeutic Equivalence Chemical Equivalence

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Disintegration of drug Dissolution of drug

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Tab/Cap. disintegration Granules disintegration Fine particles dissolution dissolution dissolution Drug in solution absorption Drug in blood, fluids, tissues

Factors affecting Bioavailability:

Factors affecting Bioavailability Dosage form related Patient related

Dosage form related factors:

Dosage form related factors 1) Physiochemical properties of drug a) Physical state – Solution>Suspension>Capsule>Tablet>Coated Tab

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b) Lipid or Water solubility c) Particle size

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d) Crystal form – e.g. Amorphous Chloramphenicol > Crystalline Chloramphenicol.

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e) Degree of hydration of crystal – e.g. Anhydrous Ampicillin > Trihydrate form f) Salt form – e.g. Pot.Peni.V > Cal.Peni.V > Peni.V

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g) Surfactant Better contact of drug solution with cell membrane due to spreading effect.

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2) Formulation and manufacturing factors A) Disintegrating agents – a) Agents which swells with moisture e.g. Starch b) Agents which melts at body temp. e.g. Cocoa butter c) Agents which effervesce with moisture e.g. Na2CO3 and tartaric acid

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B) Amount of lubricant C) Special coatings D) Compression force

Patient related factors:

Patient related factors 1) Variation in pH Acidic drugs- stomach Basic drugs - Intestine

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2) Gastric emptying rate Factor Effect 1) Increased Viscosity of stomach content Decreased 2) Stress, anxiety Decreased 3) exercise Decreased 4) Fatty meal Decreased 5) Increased pH Decreased pH Increased Decreased 6) Gastric ulcers Chrohn’s disease Hyperthyroidism Decreased Decreased Increased 7) Atropine Metoclopramide Decreased Increased

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3) First pass metabolism Low Intermediate High- not given orally High- oral dose high Phenobarbitone Aspirin Lignocaine Pethidine Tolbutamide Quinidine Isoprenaline Propranalol Theophylline Pentazocin Hydrocortisone Verapamil phenylbutazone Metoprolol Morphine Nortryptiline

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4) Age, Sex, Weight 5) Diseased State -GI diseases - Liver diseases - CHF

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5) Interactions with other substances a) Food Reduced Delayed Increased Aspirin Acetaminophen Chloroquine Ampicillin Digoxin Mefloquine Atenolol Frusemide Halofantrine Captopril Diclofenac Griseofulvin

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b) Drugs 1) Direct - Chelation of tetracyclines by metal ions in antacids -Adsorbtion of digoxin by cholestramine - Vit C increases absorption of iron 2 ) Indirect- Increased acetaminophen absoption due to metoclopramide.

Measurement of Bioavailability:

Measurement of Bioavailability Blood level data Urinary data Clinical data Pharmacological data

Methods for assessment of bioavailability:

Methods for assessment of bioavailability Sequence of events Method Example 1) Drug liberation and dissolution Dissolution rate In Vitro; Water, Buffer, Gastric fluid 2) Free drug in systemic circulation Blood level Peak level ( Cmax ) Time to peak ( Tmax ) AUC In vivo; Blood, Serum, Plasma 3) Pharmacological effect Onset of effect Duration of effect Intensity of effect In vivo; Measurement of response (BP, BSL) 4) Clinical response Observed clinical success/failure In vivo; evaluation of clinical response. 5) Elimination Amount of drug excreted In vivo; Urine.

Study Design of Bioavailability:

Study Design of Bioavailability Reference standard a) New formulation – Approved drug in market b) Controlled Release c) Combination product – Approved combination or single drug product

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Inclusion and exclusion criteria Sample size Period of trial

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Fasting/ fed condition Single Vs multiple dose method studies


Choice of parameters a) Peak height (Cmax) b) Time for peak concentration (Tmax) c) Area under curve

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AUC can be determined by – a) Using Planimeter b) Cut and Weight method c) Trapezoidal rule




References Iain L.O. Bruxton,Pharmacokinetics and Pharmacodynamics, Goodman and Gilmans ,Pharmacological basis of therapeutics;11;4-7;2005. H. Rang and M. Dale , Absoption and distribution of drugs; Pharmacology; 5,91-104

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Tripathi K.D .,Phamacokinetic- Membrane transport, absoption and distribution of drugs,Essentials of Medical Pharmacology; 6;15-8;2008. R.S.Satoskar ,General considerations and pharmacokinetics,Pharmacology and pharmacotherapeutics;21;9-13;2009

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HL Sharma, KK Sharma , Phamacokinetics,Principles of Pharmacology;1;29-34;2008 Harbert M.,Pharmacokinetics, Katzung B.G., Basis of clinical pharmacology;11;11-15;2009

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Shargel, L.; Yu, A.B.; Applied biopharmaceutics & pharmacokinetics ;New York: McGraw-Hill;4;21-34,1999.

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Thank You !!!

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