Bioavailability

This presentation explains the basic concepts of bioavailability which is an important part of pharmacokinetic studies.

1. BIOAVAILABILITY DR MRUNAL DHOLE 23-08-2016

2. LAYOUT Definition of Bioavailability History Types of Bioavailability Equivalence Measurement of bioavailability Bioequivalence and its significance Factors affecting oral bioavailability

3. BIOAVAILABILTY Bioavailability of a drug is defined as the fraction of drug or percentage of drug that reaches systemic circulation in unchanged form (fractional availability = F) According to the U.S. Food and Drug Administration (FDA), bioavailability of a drug  means 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

4. PHENYTOIN TOXICITY Sudden outbreak of phenytoin toxicity in Australia in 1968 Supply of inert excipient, calcium sulphate used in “Dilantin Sodium Capsules” (100 mg) exhausted ↓ Replaced with lactose ↓ Faster dissolution (lactose wetted easily) ↓ Quicker absorption ↓ Plasma concentration increased (normally, 10-20 µg/ml) ↓ Toxicity (posterior fossa tumor, ataxia of gait, double vision, vomiting)

5. VARIATIONS IN BIOAVAILABILITY OF DIGOXIN In 1971, patients in a New York hospital were found to require unusually large maintenance doses of digoxin A study was conducted with four healthy volunteers where they were administered standard digoxin tablets from different manufacturers Even though the digoxin content of the tablets was same, there were gross differences in the plasma concentration achieved This happened because of differences in particle size

6. TYPES OF BIOAVAILABILITY ABSOLUTE BIOAVAILABILITY Bioavailability of an orally administered drug is compared with the bioavailability obtained of the same drug when it is administered intravenously RELATIVE BIOAVAILABILITY Bioavailability of a formulation of a certain drug (A) is compared with another formulation (B) of the same drug It is used to assess the bioequivalence of two drug products

7. EQUIVALENCE BIOEQUIVALENCE Based on the plasma concentration achieved, if two or more dosage forms of a drug achieve the same bioavailability they are called bioequivalent. CHEMICAL EQUIVALENCE Based on the chemical assay if two or more dosage forms of a drug contain the same amount of drug , they are said to be chemically equivalent e.g. Crocin and Calpol tablets, both contain paracetamol (500 mg). Therefore, they can be considered as chemically equivalent.

8. THERAPEUTIC EQUIVALENCE If two different drugs produce the same therapeutic or clinical response they are called therapeutically equivalent. e.g. Imipramine , a tricyclic antidepressant and fluoxetine , a SSRI produce the same effect for the treatment of endogenous depression CLINICAL EQUIVALENCE If the response produced by two or more brands of a generic drug is same they are called clinically equivalent e.g. The response produced by Calpol ( paracetamol ) and Crocin ( paracetamol ) is same, so they are clinically equivalent

9. MEASUREMENT OF BIOAVAILABILITY After the drug is administered intravenously, its plasma concentration is measured at different intervals On a separate occasion, the drug is given orally and similar process is repeated A plasma concentration time curve is plotted for both i.v . and oral concentration. The areas under these plasma concentration time curves is measured. Bioavailability of the drug is calculated using the following formula F = AUC(oral) x 100/AUC( i.v .)

10. AUC = Area under Curve C max = Peak plasma concentration T max = Time to attain peak plasma concentration

11. MEASUREMENT OF AUC AUC is calculated using the Trapezoidal rule It consists in dividing the plasma concentration-time profile into several trapezoids and calculating the AUC by adding the area of these trapezoids It is expressed as mg x h/L

12. AREA UNDER CURVE Area under curve is dependent on the clearance of the drug and the dose administered For a drug that follows first order elimination, AUC is directly proportional to the dose AUC is inversely proportional to the clearance of the drug

13. BIOAVAILABILITY AND BIOEQUIVALENCE For a generic formulation of a drug to be considered bioequivalent to the patented one, the AUC , C max and T max of both the formulations must be identical Differences of less than 25% in bioavailability among different formulations of one drug will have no significant effect on clinical outcome, hence they are accepted as bioequivalent.

14. SIGNIFICANCE OF BIOEQUIVALENCE Two different brands of the same drug need to be bioequivalent when the drug obeys zero-order or mixed-order elimination kinetics has a narrow therapeutic index If a patient is switched from one brand to another that are not bioequivalent, two outcomes are possible: Therapeutic failure due to decreased bioavailability OR Drug intoxication due to increased bioavailabilty

15. FACTORS AFFECTING ORAL BIOAVAILABILITY Pharmaceutical Particle size Drug as a salt Drug as a crystal Excipients and Adjuvants Lipid solubility & degree of ionisation Pharmacological Route of administration Gastric emptying and gut motility Gastrointestinal disease Food Drug-Drug interactions Pharmacogenetic factors Splanchnic blood flow Hepatic first pass metabolism

16. DISINTEGRATION AND DISSOLUTION

17. PHARMACEUTICAL FACTORS

18. 1. PARTICLE SIZE Decrease in particle size ↓ Increase in surface area ↓ Rapid dissolution of the drug ↓ Increased bioavailability Poorly soluble, slowly dissolving drugs are often marketed in microfined form e.g., Aspirin, spironolactone , griseofulvin , digoxin

19. 2. SALT FORM Salts of weakly acidic drugs highly water soluble ↓ Free acidic drug from these salts precipitate in microcrystalline form ↓ Faster dissolution rate ↓ Increased bioavailability e.g. Tolbutamide sodium and phenytoin sodium have better bioavailability than tolbutamide and phenytoin as free drugs.

20. 3. CRYSTAL FORM Sometimes the amorphous and anhydrous forms of drugs have faster dissolution rate and thus have better bioavailability than their crystalline form E.g., Amorphous chloramphenicol palmitate Anhydrous forms of caffeine, theophyliine and ampicillin

21. 4. EXCIPIENTS AND ADJUVANTS Inert materials are added for various purposes. Filling materials to increase the amount of drug – starch, calcium sulfate Binding agents – gum Wetting agents – lactose, polysorbate 80 Lactose and polysorbate 80 → increase solvent penetration and reduce particle aggregation → faster dissolution → increased absorption

22. 5. LIPID SOLUBILITY AND IONISATION The less ionized the drug is, the more is the lipid solubility → better absorption Weakly acidic drugs are lipid soluble at acidic pH → absorbed from stomach e.g., aspirin Weakly basic drugs are lipid soluble at basic pH → absorbed from ileum e.g., pethidine Strong acids and bases are permanently ionized → not absorbed on oral administration e.g., heparin, succinylcholine Non-polar drugs are incapable of ionization → highly lipid soluble → easily absorbed e.g., prednisolone, digoxin, chloramphenicol

23. PHARMACOLOGICAL FACTORS

24. 1. ROUTE OF ADMINISTRATION Route of administration Bioavailability (%) Characteristics Intravenous (IV) 100 (by definition) Most rapid onset Intramuscular (IM) 75 to ≤100 Large volumes, often feasible; may be painful Subcutaneous (SC) 75 to ≤100 Smaller volumes than IM; m ay be painful Oral (PO) 5 to <100 Most convenient; first pass effects may be significant Rectal (PR) 30 to <100 Less first pass effects than PO Inhalation 5 to <100 Often very rapid onset Transdermal 80 to ≤100 Very slow absorption; used for lack of first pass effect; prolonged duration of action

25. 2. GASTRIC EMPTYING AND GUT MOTILITY Accelerated gastric emptying → Drug reaches the large absorptive surface of small intestine sooner → Increased absorption and thus increased bioavailability Stasis in diseases such as diabetic neuropathy, migraine and use of anticholinergics → retarded gastric emptying → Decreased absorption Metoclopromide stimulates gastric emptying → Increased absorption of paracetamol in migraine Excessive peristaltic activity (as in case of diarrhoea ) impairs absorption

26. GASTRIC EMPTYING Promoted by Fasting Anxiety Lying on the right side Hyperthyroidism Drugs like metoclopramide Retarded by Fatty diet Endogenous depression Lying on the left side Hypothyroidism Drugs like atropine, imipramime , chlorpromazine

27. 3. GASTROINTESTINAL DISEASE Gastroenteritis - decreased absorption of drugs in general Pyloric stenosis → retards gastric emptying → reduced absorption Coeliac disease Amoxycillin , pivampicillin – impaired absorption Cephalexin – increased absorption Ampicillin – no change Crohn’s disease Trimethoprim – decreased absorption Sulfamethoxazole – increased absorption

28. 4. FOOD Absorption is favoured by an empty stomach in case of thyroxine and rifampicin Absorption of propranolol and lithium is increased after food intake Absorption of griseofulvin is increased after intake of fatty meal Vitamin C increases the absorption of iron by reducing it in ferrous (Fe + ) form Absorption of tetracyclines is markedly reduced if taken with milk or milk products

29. 5. DRUG-DRUG INTERACTIONS Drug-Drug interactions that decrease bioavailability Liquid paraffin emulsifies fats → No absorption of fat soluble vitamins (A,D,K and E) Aluminium , calcium and magnesium present in antacids bind with tetracyclines Iron present in haematinics ↓ formation of a chelated complex ↓ poorly absorbed Drug-Drug interactions that increase bioavailability Probenecid → Blocks excretion of penicillin → Increased bioavailability

30. 6. SPLANCHNIC BLOOD FLOW Increased after food consumption → Higher plasma concentration of drugs, e.g. propranolol Decreased in hypovolaemia → reduces drug absorption, e.g. heart failure

31. 7. PHARMACOGENETIC FACTORS Acetylation of INH Can be slow or rapid Slow acetylation ↓ High bioavailability ↓ INH induced peripheral neuritis (Israelis, Scandinavians) Rapid acetylation ↓ Increase in hepatotoxic metabolites ↓ Low bioavailability (Chinese, Japanese and 40% of Indians, an autosomal recessive trait) Hydrolysation of Succinylcholine Presence of atypical plasma pseudocholinesterase in some individuals ↓ Succinylcholine hydrolysed very slowly ↓ 1/6 th of the normal dose enough to provide the same therapeutic effect

32. 8. FIRST PASS METABOLISM

33. HOW DOES FIRST PASS METABOLISM AFFECT BIOAVAILABILITY? Effect of first pass metabolism on bioavailability is expressed as the extraction ratio (ER) ER = CL liver / Q where Q = Hepatic blood flow (normally 90 L/ hr in a person weighing 70 kgs ) Oral bioavailability of a drug can be determined from the extraction ratio . F = f x (1 – ER) where f = Extent of absorption

34. BIOAVAILABILITY OF MORPHINE For morphine, CL liver = 60 L/h/70 kg Q = 90 L/h/70 kg ER = CL liver / Q Thus, ER morphine = 60/90 = 0.67 Since morphine is almost completely absorbed f = 1 F = f x (1 – ER) Thus, F morphine = (1- 0.67) = 0.33 = 33%

35. Drugs with high extraction ratio (ER) have low oral bioavailability e.g. morphine, lidocaine , verapamil Increase in dose can help reach therapeutic plasma concentrations by oral route of administration However there will also be an increase in the concentration of drug metabolites compared to intravenous administration ↓ Toxicity e.g. Lidocaine on oral administration causes central nervous toxicity

36. ORAL BIOAVAILABILITY OF SOME DRUGS Oral Bioavailability Drugs Negligible Heparin, gentamicin , d- tubocurarine 15-20% Morphine, glyceryl trinitrate , isoprenaline , pentazocine 50-70% Atenolol , nifedipine , digoxin , propranolol >90% Chloroquine , paracetamol , phenytoin , warfarin , sodium valproate <=100% Diazepam, lithium, indomethacin , tamsulosin

37. REFERENCES Buxton ILO, Benet LZ. Pharmacokinetics: The dynamics of drug absorption, distribution, metabolism, and elimination. In: Brunton LL, Chabner B, Knollman B, editors, 12 th ed. Goodman Gilman’s The pharmacological basis of therapeutics. New York: McGraw-Hill Medical publishing division; 2011; p. 17-40. Katzung BG, Trevor AJ. Pharmacokinetics & pharmacodynamics: Rational dosing & the time course of drug action. In: Holford NHG, 13 th ed. Basic and clinical pharmacology. New York. McGraw- Hill Education; 2015; p. 37-52. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G. Drug absorption and distribution. In: Rang HP, Dale MM, 7 th ed. Rang and Dale’s pharmacology. Spain: Elsevier Inc ; 2012; p. 99-114. Satoskar RS, Rege NN, Bhandarkar SD. General considerations and pharmacokinetics. In: Tripathi R, Satoskar RR, 23 rd ed. Pharmacology and pharmacotherapeutics . Mumbai. Popular Prakashan Private Limited; 2013; p. 1-26. Sharma HL, Sharma KK. Pharmacokinetics. In: Sharma HL, 2 nd ed. Principles of Pharmacology. Hyderabad. Paras Medical Publisher; 2013; p. 25-55. Srivastava SK. Routes of drug administration & pharmacokinetics. In: Srivastava SK, 1 st ed. A Complete Textbook of Medical Pharmacology. Sirmour . Avichal Publishing Company; 2014; p. 15-64.

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