bioavailability

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BIOAVAILABILITY:

BIOAVAILABILITY Dr. JEEVAN JACOB Junior Resident Dept. of Pharmacology

Definition :

Definition “The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action” US FDA Code of Federal Regulations Title 21 , 320.1(a)

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Bioavailable fraction (F), refers to the fraction of administered dose that enters the systemic circulation in unchanged form F = Bioavailable dose Administered dose

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Factors affecting Bioavailability of a Drug Pharmaceutical Factors 2. Pharmacological factors

Pharmaceutical Factors :

Pharmaceutical Factors Drug administered DISINTEGRATE DISSOLVE Gets Absorbed Tab/ cap Powders & Suspensions

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These depends on Particle size - smaller the size, faster the dissolution and thus the absorption E.g. Microfined Aspirin Form - Amorphous form gets absorbed faster than crystalline form E.g. Amorphous Chloramphenicol

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Degree of Ionization - Unionized form penetrates the GI mucosal lining quickly Weakly acidic drugs: Aspirin, Barbiturates→ Stomach, duodenum Weakly basic drugs: Pethidine , Ephedrine→ Small intestine Strongly acidic / basic drugs: H ighly ionized & poorly absorbed

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Salt Form Gets absorbed faster E.g. Phenytoin Sodium Water of hydration anhydrous forms gets absorbed faster

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Nature of Excipients and Adjuvant -They are used as filling materials -Binding agents or to get target size Eg . Lactose, Polysorbate 80 etc are wetting agents which enhance solvent penetration in drug particles and minimize aggregation of particles

Outbreak of Phenytoin toxicity in epileptic patients in Brisbane, Australia during 1968:

Outbreak of Phenytoin toxicity in epileptic patients in Brisbane, Australia during 1968 50 Pts developed Phenytoin toxicity In them the blood phenytoin levels were above the therapeutic range. The excipient in the responsible phenytoin capsules had been changed several months before the outbreak This change was probably causing the altered blood phenytoin concentrations.

Pharmacological Factors:

Pharmacological Factors Gastric Emptying and GI motility Faster the Gastric Emptying, faster it reaches the small Intestine with large surface area by Fasting, anxiety Hyperthyroidism by Fatty diet, Depression, Anticholinergic drugs

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Gastro Intestinal disease Eg . Celiac Sprue - Malabsorption of fat Amoxicillin absorption Cephalexin absorption Ampicillin absorption

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Gastro Intestinal disease Eg . Crohn’s Disease TMP absorption SMX absorption

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Food -Usually empty stomach favors absorption -Some drugs like Griseofulvin , absorption is enhanced by Fatty meal -Vitamin C ↑ Iron absorption, Phytates retard it - Calcium ↓ absorption of Tetracyclines

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Drug Interaction - Liquid Paraffin Emulsifies fat and thus decrease absorption of Vitamins ADEK -Antacids with Ca, Mg, Al etc can reduce the BA of Tetracyclines

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First pass metabolism Gut wall (e.g. Isoprenaline ) Liver (e.g. Opoids , ß-blockers, Nitrates)

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Pharmacogenetic Factors Genetically mediated variations in drug response Eg . G6PDH deficiency causes hemolysis with Oxidant drugs like Primaquine,INH , Nalidixic acid, Menadione etc

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Pseudo cholinesterase deficiency causes prolonged apnoea with Succinyl choline Acetylator polymorphism FAST ACETYLATORS SLOW ACETYLATORS SHIP – Sulfa, Hydralazine , INH, Procainamide

Representation of Bioavailability Data:

Representation of Bioavailability Data C max T max AUC time concentration

Representation of Bioavailability Data:

22 Representation of Bioavailability Data Construction of plasma concentration vs time curve. Initial rise in curve indicates that drug is absorbed at a faster rate than it is metabolized or excreted. (absorption phase) It continues to rise until a peak conc. is obtained ( C max ) - rate of absorption = rate of excretion.

Representation of Bioavailability Data(cont’d):

23 Representation of Bioavailability Data(cont’d) At the beginning of the descending portion of the curve, both absorption and elimination is taking place - elimination is faster. After a time absorption ceases and the conc. of drug in plasma is determined only by the rate of elimination. (the elimination phase of the curve)

Absolute bioavailability:

24 Absolute bioavailability It is measured by comparing the area under the drug concentration–time curve after extravascular administration to that after IV administration

IV bolus:

25 IV bolus Area under concentration curve (AUC)

Oral dosage form :

26 Oral dosage form Area under concentration curve (AUC)

Absolute bioavailability:

27 Absolute bioavailability For the same dose (IV vs. Oral), the bioavailability is given by:

Relative bioavailability:

28 Relative bioavailability The relative bioavailability is the systemic availability of a drug product ( A ) compared to another drug product ( B ).

Oral dosage form (product A):

29 Oral dosage form (product A) Area under concentration curve (AUC)

Oral dosage form (product B):

30 Oral dosage form (product B) Area under concentration curve (AUC)

Relative bioavailability:

31 Relative bioavailability For the same dose (IV vs. Oral), the bioavailability is given by:

Measurement of bioavailability:

32 Measurement of bioavailability Pharmacokinetic methods ( indirect ) 1. Blood analysis 2. Urinary excretion data Pharmacodynamic methods ( direct ) 1. Acute pharmacological response 2. Therapeutic response

1.Blood analysis:

33 1.Blood analysis The plasma concentration – time curve A direct relationship exists between the concentration of drug at the site of action & concentration of drug in the plasma. Serial blood samples are taken after drug administration & analyzed for drug concentration.

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Parameters determined:

35 Parameters determined Peak Plasma Concentration ( C max ) Time of Peak concentration ( t max ). Area Under Curve (AUC) Minimum Effective Concentration (MEC) Maximum Safe Concentration (MSC) Onset of action. Duration of action Pharmacokinetic parameters Pharmacodynamics parameters

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36 AUC or Extent of absorption can be measured by many methods… 1. Planimeter Instrument for mechanically measuring the area 2 . Cut & weigh method AUC is cut & weighed on analytical balance. The weight obtained is converted to proper unit by dividing it by the weight of a unit area of same paper.

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3. Trapezoidal method 4. Plotting Graph on Rectilinear graph paper 5. Using a Transparency with a preprinted grid

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AUC 2-3 = Cp 2 + Cp 3 x (t 3 - t 2 ) 2 AUC: Trapezoidal Rule

2. Urinary excretion data:

39 2. Urinary excretion data The is another method of determination of bioavailability provided that the active ingredient is excreted unchanged in the significant quantity of urine. The cumulative amount of active drug excreted in urine is directly proportional to extent of systemic drug absorption. The rate of drug excretion is directly proportional to rate of systemic drug absorption.

Advantages of Urinary excretion data:

40 Advantages of Urinary excretion data Useful when there is lack of sufficiently sensitive analytical techniques to measure concentration of drug in plasma. Noninvasive method therefore better subject compliance. Convenience of collecting urine samples in comparison to drawing of blood periodically. If any case the urine drug concentration is low, assaying of larger sample volume is done. Direct measurement of bioavailability, both absolute & relative is possible

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42 Bioavailability is determined by…. F = (U ) oral . D IV (U ) IV . D oral U = Cumulative amt of unchanged drug excreted in urine D IV = IV dose D oral = oral dose F = absolute bioavailability

Pharmacodynamic methods ( direct ) :

Pharmacodynamic methods ( direct ) 1. Acute pharmacological response 2. Therapeutic response 43

1. Acute pharmacological response :

1. Acute pharmacological response Bioavailability can be determined from the acute pharmacologic effect – time curve as well as from dose response graph. E.g.: pupil diameter, heart rate or BP can be useful as an index of drug bioavailability DISADVANTAGE is that pharmacological response tends to be more variable and thus accurate correlation between the measured response and drug available from the formulation is difficult

2.Therapeutic response :

45 2.Therapeutic response This method is based on the observing the clinical response to a drug formulation given to a patients suffering from disease for which it is intended to be used. Eg . For anti inflammatory drugs, the reduction in the inflammation is determined. The major DRAWBACK is quantification of observed response is too improper to allow for reasonable assessment of relative bioavailability between two dosage forms of a same drug.

BIOEQUIVALENCE:

BIOEQUIVALENCE “Two preparation of drug are considered bioequivalent when the rate and extend of bioavailability of active drug from other is not significantly different under suitable condition”

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So if the plasma level profiles of two dosage forms of same drug are comparable and super imposable And their BA difference is not more than 20-25%

Chemical Equivalence:

Chemical Equivalence If two or more dosage forms of same drug contain same labeled quantities of drug as prescribed in pharmacopeia, they are chemically equivalent E.g. Dilantin and Eptoin

Clinical Equivalence:

Clinical Equivalence Two drugs are said to be clinically equivalent if they provide identical in vivo pharmacological response E.g. Dilantin and Eptoin

Therapeutic Equivalence:

Therapeutic Equivalence If structurally different drugs can provide same therapeutic response as another drug, then they are called therapeutically equivalent Eg : Trifluperazine { Phenothiazine } may be TE to Haloperidol { Butyrophenol } in treating schizophrenia

Reference:

Reference Essentials of Medical Pharmacology, 7 th Ed. KDT Principles of Pharmacology, 2 nd Ed. Sharma & Sharma Text book of Medical Pharmacology, 1 st Ed. Srivastava www. fda . gov

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