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

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

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

Absorption & distribution Elimination Sites of Administration

- Plasma ( 5 % of body weight = 4 liters ). 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.

(60% of body weight in 70-kg individual) 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)

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

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.

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.

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

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

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.

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).

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.

Binding of Drugs Plasma proteins binding. Tissue proteins binding.

Plasma protein binding Drugs can bind to plasma proteins (acidic drug bind to albumin while basic drugs bind to glycoprotein) Drugs exist in two forms bound and unbound forms in equilibrium Unbound drug (free) bound drug

Plasma protein binding and drug distrubution Drug + Protein ⇄ Drug-Protein Complex (Active, free) (Inactive, bound) Competition between drugs for plasma protein-binding sites may increase the "free fraction," possibly enhancing the effects of the drug displaced. Example: sulfonamides and bilirubin in a neonate

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

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

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

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.

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.

Bioavailability Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action I.V. provides 100% bioavailability i.e F= 1. Subcutaneous, intramuscular, oral, rectal, and other extravascular routes of administration require that the drug be absorbed first, which can reduce bioavailability. Bioavailability (F) = AUC oral AUC IV

Absolute bioavailability Absolute bioavailability: The bioavailability of a drug product is compared to its intravenous standard formulation. complete concentration-time profiles are needed for both the intravenous and other routes of administration.

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

Relative bioavailability is important to get an idea of how formulations or routes of administration differ dosage adjustment when changing formulations or routes of administration. Pharmaceutical industries conduct bioequivalence studies for their new product to decide on formulation for the clinical use.

Bioequivalence Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration. 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.

Molecular weight of drug. Drug Formulation (rate of dissolution). Factors Affecting Bioavailability: 1. Drugs Molecular weight of drug. Drug Formulation (rate of dissolution). (solution > suspension > capsule > tablet) Drug solubility of the drug Chemical instability in gastric pH (Penicillin & insulin )

First pass metabolism First pass metabolism For example, when the B–blocking agent propranolol is given intravenously, its bioavailibilty is 100% but when it is given orally approximately 20% of the administered dose reaches the systemic circulation as intact drug due to first pass metabolism.

First pass metabolism

Greater blood flow increases bioavailability Factors Affecting Bioavailability (BAV): Blood flow to absorptive site Greater blood flow increases bioavailability Intestine has greater blood flow than stomach Surface area available for absorption. Intestinal microvilli increases it Rate of gastric emptying rapid gastric emptying fast transit to intestine pH of gut

Diarrhea reduce absorption Intestinal motility (Transit Time) Diarrhea reduce absorption Drug interactions Food slow gastric emptying generally slow absorption