Pharmacokinetics II: Bioavailability and Distribution

1. Pharmacokinetics II: Bioavailability and Distribution Prof. Hanan Hagar Pharmacology Department

2. Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action I.V. provides 100% bioavailability. Oral usually has less than I.V. Bioavailability

3. Absolute Bioavailability The bioavailability of a drug product is compared to its intravenous standard formulation.

4. Relative Bioavailability This calculation is determined when two products are compared to each other, not to an intravenous standard . E.g Tylenol (paracetamol 500 mg) compared to panadol (paracetamol 500 mg)

5. Relative Bioavailability This is commonly calculated in the generic drug industry to determine that the generic formulation (e.g., a tablet) is bioequivalent to the original formulation (e.g., another tablet). Pharmaceutical industries conduct bioequivalence studies for their new product to decide on formulation for the clinical use.

6. Bioequivalence Two drug products are considered to be bioequivalent when the rates and extents of bioavailability of the active ingredient in the two products are not significantly different under suitable test conditions.

7. Distribution What student should know • Major body fluid compartments • Concept of compartments. • Apparent volume of distribution (vd). • Plasma protein binding. • Tissue binding. • Redistribution

8. Distribution Is the process by which drugs leave blood circulation and enters the interstitium and/or the cells of the tissues.

9. Absorption & distribution Elimination Sites of Administration

10. The major body fluid compartments are Extracellular fluid (22%) - Plasma ( 5 % of body weight = 4 liters ). - Interstitial fluid ( 16 % = 10 liters). - Lymph ( 1 % ). Intracellular fluid ( 35 % ) fluid present inside all cells in the body (28 L). Transcellular fluid ( 2%) cerebrospinal, intraocular, synovial, peritoneal, pleural & digestive secretions.

11. Total body fluids (60% of body weight in 70-kg individual) Plasma (4 L) Interstitial fluids (10 L) Intracellular volume ( 28 L) Total body Fluids (42 Liters)

12. Apparent Volume of Distribution (Vd) is the ratio of drug amount in the body to the concentration of drug in blood Vd (L)= total amount of drug in body (mg) concentration in blood (mg/L) Large Vd = means long duration of action

13. FACTORS AFFECTING DISTRIBUTION 1.Cardiac output and blood flow. 2. Physiochemical properties of the drug. • Molecular weight • Pka. • Lipid solubility. 3. Capillary Permeability 4. Plasma protein binding 5. Tissue binding.

14. Blood flow to organs • The greater the blood flow to tissues, the more distribution that occurs from plasma to interstitial fluids. • Drugs distribute more rapidly to brain, liver and kidney > more than skeletal muscles & fat.

15. Physiochemical properties • Most lipid soluble drugs cross biological membranes • Hydrophilic drugs do not readily cross membranes but go through slit junctions

16. Volume of Distribution (Vd) Drugs with high Vd • Have higher concentrations in tissues than in plasma. • Relatively lipid soluble. • Distributed intracellularly • Not efficiently removed by haemodialysis. • e.g. phenytion, morphine, digoxin

17. Volume of Distribution (Vd) Drugs with low Vd • confined to plasma & interstitial fluid. • distributed in extracellular compartments. • Polar comp or lipid insoluble drugs. e.g. Carbenicillin, vecuronium, gentamycin. • High MW e.g. heparin – insulin. • High plasma protein binding e.g. warfarin. • Do not cross BBB or placental barriers.

18. Capillary permeability • Endothelial cells of capillaries in tissues other than brain have wide slit junctions allowing easy movement & distribution. • Brain has tight junction Blood Brain Barrier (BBB).

19. Blood brain barrier (BBB): • Only lipid soluble drugs or carrier mediated transport can cross BBB. • Hydrophilic drugs (ionized or polar drugs) can not cross BBB. • Inflammation as in meningitis increase permeability to hydrophilic drugs • e.g. penicillin & gentamycin Placental barrier • Lipid soluble drugs can cross placental barrier and enter the fetal blood.

24. Binding of Drugs • Plasma proteins binding. • Tissue proteins binding.

25. Plasma protein binding • Drugs can bind to plasma proteins (acidic drug bind to albumin while basic drugs bind to glycoprotein). • Drug + Protein ⇄ Drug-Protein Complex • (unbound) (bound) • Drugs exist in two forms bound and unbound forms in equilibrium Unbound drug (free)bound drug

26. Unbound form of drug • diffusible form • combine with receptors • available for elimination • has short duration of • action (t ½). bound form of drug • non diffusible form • can not combine with receptors • not available for elimination • has long duration of action (t ½).

27. Characters & consequences of Binding • Usually reversible. • determines volume of distribution (vd) • Slows drug metabolism & excretion. • Prolongs duration of drug action (t1/2). • Result in clinically important drug interactions.

28. Displacement Competition for the same binding site on the plasma proteins may occur between two drugs  displacement of one drug & increasing its "free fraction” and effects. Aspirin +Albumin-warfarin Albumin-aspirin+ free warfarin bleeding.

29. Another example: sulfonamides and bilirubin in a neonates (hyperbilirubinemia).

31. Tissues Binding Drugs can bind to specific tissue Tetracycline bind to bone Iodides accumulate in salivary & thyroid glands

32. Redistribution Redistribution of the drug away from its site of action to other tissues where it can not produce an action e.g. thiopental Termination • Biotransformation. • Excretion. • Redistribution.