Pharmacology Department
Pharmacokinetics II: Bioavailability and Distribution Prof. Hanan Hagar Dr. Ishfaq Bukhari Pharmacology Department By the end of the lectures, students should be able todefine thefollowing:
Major body fluid compartments Concept of compartments. Apparent volume of distribution (vd). Plasma protein binding. Tissue binding. Bioavailability of drugs Bioavailability Is the fraction of unchanged drug thatenters systemic circulation afteradministration and becomes available toproduce an action (therapeutic effect) i.e the rate (time) and extent (amount) ofdrugs reaching systemic circulation. Bioavailability (F) = AUC(oral)X100 AUC(I.V.) Bioavailability I.V. provides 100% bioavailability i.e. F= 1. Subcutaneous, intramuscular, oral, rectal, andother extra vascular routes of administrationrequire that the drug be absorbed first, whichcan reduce bioavailability. Absolute bioavailability
The bioavailability of a drug afteradministration by any route is compared to itsintravenous standard formulation. Pharma industries usually determineabsoulute bioavailibility by giving drugorally and compared to the same drugstandard preparation given byintravenously Relative bioavailability
is determined when two products arecompared to each other, not to an intravenousstandard. This is commonly calculated in the drug industryto determine that the generic formulation isbioequivalent to another formulation. e.g Tylenol (paracetamol 500 mg) compared topanadol (paracetamol 500 mg). Relative bioavailability
is important to getan idea of how differentformulations or routes of administration differin their bioavailability. dosage adjustment is required when changingformulations or routes of administration. Bioequivalence Two drug products are considered tobebioequivalentwhen the rates and extents ofbioavailability of the two products are notsignificantly different under suitable testconditions. Rate and extent means the amount of drugsand the time required reaching the systemiccirculation. Factors affecting bioavailability:
are the same factors controlling drug absorption GENERAL FACTORS lipid solubility Degree of ionization Drug solubility (aqueous sol better than oily,susp,sol) Dosage forms (depending on particle size anddisintegration) Concentration of drugs Circulation at site of absorption Area of absorbing surface (small intestine has largesurface area) Route of administration. Distribution Distribution Is the process by which drugs leave bloodcirculation and enters the interstitiumand/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). Transcellularfluid ( 2%) cerebrospinal, intraocular, synovial, peritoneal,pleural & digestive secretions. (70% of body weight in 70-kg individual)
Total body fluids (70% 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 tothe 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 fromplasma to interstitial fluids. Drugs distribute more rapidly to brain,liver and kidney > more than skeletalmuscles & fat. Physiochemical properties
Most lipid soluble drugs cross biologicalmembranes Hydrophilic drugs do not readily crossmembranes 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. distributedin extracellular compartments. Polar comp or lipid insoluble drugs. e.g.Carbenicillin,vecuronium, gentamycin. High MWe.g. heparin insulin. High plasma protein binding e.g. warfarin. Do not crossBBB or placentalbarriers. Capillary permeability
Endothelial cells of capillaries in tissuesother than brain have wide slit junctionsallowing easy movement & distribution. Brain has tight junction Blood BrainBarrier (BBB). Blood brain barrier (BBB):
Only lipid soluble drugs or activelytransported drugs can cross BBB. Hydrophilic drugs (ionized or polar drugs)can not cross BBB. Inflammationas in meningitis increasepermeability to hydrophilic drugs e.g. penicillin & gentamycin Placental barrier Lipid soluble drugs can cross placentalbarrier and enter the fetal blood. Binding of Drugs Plasma proteins binding. Tissue proteins binding. Plasma Proteins Albumin Has affinity for acidic drugs as warfarin,phenytoin, aspirin Glycoprotein Has affinity for basic drugs (cationic) asdiazepam, quinidine. Plasma protein binding
Drugs can bind to plasma proteins (acidic drugbind to albumin while basic drugs bind toglycoprotein) Drugs exist in two forms bound and unboundforms in equilibrium Unbound drug (free) bound drug 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 inactive not available for metabolism & excretion has long duration of action (t ). Unbound form of drug diffusible form combine with receptors active available for metabolism & excretion has short durationof action (t ). Binding of drugs and its effect on drug action
Usually reversible. determines volume of distribution (vd) Slows drug metabolism & excretion. Prolongs duration of drug action (t1/2). Result in clinically important druginteractions. Displacement Competition for the samebinding site on theplasmaproteins may occur between two drugs displacement of one drug & increasingitsconcentrations & effects. Aspirin + Albumin-warfarin Albumin-aspirin +free warfarin bleeding.