Bioavailability

Bioavailability of drugs

1. Bioavailability Dr.Muhammad Usman Khalid DPT,MS-NMPT

2. Bioavailability It the fraction of drug that reaches the systemic circulation in a chemically unchanged form, following administration by any route

3. Bioavailability & route of administration I/V route = unity (one) or 100 % By any other route may be less than 100 % I/M --- 75 to ≤ 100 SC --- 75 to ≤ 100 Oral --- 5 to ≤ 100 Rectal --- 30 to ≤ 100 Inhalation --- 5 to ≤ 100 Transdermal --- 80 to ≤ 100

4. How bioavailability is measured It is measured by determining the plasma drug concentration versus time curves in a group of subjects following oral and (on separate occasion) I/V administration.

5. How bioavailability is measured Bioavailability = AUC oral / AUC intravenous AUC --- area under the blood concentration curve

6. Factors affecting bioavailability Factors which reduce the bioavailability to < 100 % Reduced absorption from the site of administration First pass elimination --- Drug undergoes metabolism or elimination prior to entering the systemic circulation

7. Factors affecting the rate and extent of absorption Nature of drug formulation Chemical instability Solubility of the drug

8. Chemical instability Unstable in the pH of gastric contents --- penicillin G Destroyed in the GI tract by enzymes --- insulin

9. Solubility of the drug Very hydrophilic drugs --- Poorly absorbed ---unable to cross lipid rich cell membranes Extremely hydrophobic --- Poorly absorbed --- cannot gain access to the surface of the cells Largely hydrophobic, yet have some solubility in aqueous solutions --- Readily absorbed

10. Pharmaceutical formulation and bioavailability A drug is incompletely released from its dosage form because of differences in the pharmaceutical formulation unrelated to the chemistry of the drug Particle size, salt form, enteric coating, crystal polymorphism, compression pressure during manufacturing, moisture content

11. Pharmaceutical formulation and bioavailability The special formulations may alter absorption “slow release” or “sustained-release” formulation “Enteric coating” prevents breakdown of tablets by acid pH of the stomach

12. “First-pass” effect “ presystemic elimination” or “first pass elimination” The elimination in the intestine and liver, which reduces the amount of drug delivered to the systemic circulation

13. Elimination in the intestine Excretion back into the intestinal lumen Metabolism

14. In the liver Metabolism Excretion into the bile

15. First pass hepatic metabolism If a drug is metabolized by the liver, the amount of drug that reaches the systemic circulation is decreased Significant biotransformation during a single passage through the liver Propranolol and lidocaine

16. Extraction ratio The effect of first pass hepatic elimination on bioavailability is expressed as the extraction ration CL liver ER = -------------------- Q (hepatic blood flow)

17. Drugs with high extraction ratio by the liver Propranolol Isoniazid Verapamil Morphine TCAs

18. Drugs that are poorly extracted by the liver W arfarin Diazepam Phenytoin Theophyllin Toulbutamide and Chlorpropamide

19. Variation in Extraction ratio Marked variation in bioavailability between subjects because of differences in hepatic function and blood flow .

20. Alternative routes of administration are used to avoid the first pass effect Parenteral routes --- Provides direct access to systemic – not portal vein “Intra” --- Three common routes --- IV, IM, SC Topical --- To maximize concentration at site of action and minimize it elsewhere Transdermal -- To prolong the duration of drug absorption

21. Alternative routes of administration are used to avoid the first pass effect By inhalation S/L absorption provides direct access to systemic – not portal vein P/R Lower rectum --- into inferior vena cava Upper rectum – to the liver

22. Significance of bioavailability Bioavailability influence the clinical effectiveness of a drug

23. Bioavailability – and route of administration Drugs that undergo near-complete presystemic metabolism and thus cannot be administered orally --- nitroglycerine – given by sublingual or transdermal route

24. Bioavailability – dose of the drugs Drugs with extensive presystemic metabolism can still be administered by the oral route, using much higher doses Verapamil – I/V – 1-5 mg, orally 40-120 mg Low dose aspirin --- result in exposure of cyclooxygenase in platelets in portal vein to the drug, but systemic sparing because of first-pass aspirin deacylation in the liver

25. Bioequivalence / bioinequivalence For comparison of the bioavailability of the “Generic equivalent of patented products” Different pharmaceutical formulation of the same drug , are given at same dose, by the same mode and their bioavailability is compared

26. V ariation in oral absorption among different formulation of digoxin

27. Bioequivalence When different pharmaceutical preparations have same bioavailability and the same rate of absorption. When this occurs, the plasma levels of the two products will be super imposable

28. Bioinequivalence When different pharmaceutical preparations are given and there is significant difference in the bioavailability & rate of absorption When this occurs, the plasma levels of the two products will not be super imposable

29. Therapeutic equivalence Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety Clinical effectiveness Maximum serum drug concentration Time required (after administration) to reach peak concentration

30. Bioequivalent VS Therapeutic equivalence Two drugs that are bioequivalent may not be therapeutically equivalent.

31. Bioavailability differences between three preparations of a drug containing the same amount

32. Bioavailability differences between three preparations of a drug containing the same amount Bioavailability A = B (A AUC = B AUC )

33. Bioavailability differences between three preparations of a drug containing the same amount Bioavailability A = B (A AUC = B AUC ) B may not produce the therapeutic effect

34. Bioavailability differences between three preparations of a drug containing the same amount Bioavailability A = B (A AUC = B AUC ) B may not produce the therapeutic effect C lower bioavailability

35. Rates of absorption Time Effect of rate of absorption on plasma concentration

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