Absorption_'24.pptx

Absorption-Distribution April 12th, 2024 Processes for drugs to reach their targets Absorption - the movement of the drug from the site of application into the blood Passage from oral → intestinal epithelial cell walls Distribution - the movement of the drug from the blood to its site of action or s...

Absorption-Distribution April 12th, 2024 Processes for drugs to reach their targets Absorption - the movement of the drug from the site of application into the blood Passage from oral → intestinal epithelial cell walls Distribution - the movement of the drug from the blood to its site of action or storage Passage from capillary beds → tissues Absorption  Compounds given orally must be able to be absorbed from the GI Tract.  A compound must have the proper balance between water and fat solubility.  Too polar (hydrophilic) and the compound will fail to pass through the fatty cell membranes  Too fatty (hydrophobic) and the compound will be poorly soluble in the gut and dissolve in fat globules. Processes by which molecules cross membranes Passive diffusion Facilitative diffusion & Active transport Paracellular Endocytosis Apical basolateral Drug molecules encounter several membrane barriers in living systems: Gastrointestinal epithelial cells, blood capillary wall, hepatocyte membrane, glomerulas, restrictive organ barriers (i.e. blood brain barrier) and a target cell membrane Most important mechanism for drug delivery is Passive Diffusion. Lipophilic molecules typically are more permeable than ionized or polar molecules Plasma Membrane SELECTIVELY PERMEABLE: Lipophilic molecules can pass through by passive diffusion. Does not let large, charged (-) or polar things through without a protein channel, transporter. Cell Membranes Phospholipids Typical Membrane Passive Diffusion is movement of very small lipid soluble molecules. The molecules move from an area of [high] to [low]. Amphipathic Distribution from Blood Stream to Site of Action  Compounds travel to organs & tissues via capillaries.  Must be able to exit/permeate the capillaries to reach the desired area and in sufficient concentration to elicit the desired pharmacological effect.  Pores can be 90-150 Å in diameter Protein Plasma Binding-Serum Albumin  6-8% of plasma is made up of proteins, many of which serve as carriers for naturally occurring compounds (steroids, fatty acids and thyroid hormones etc..)  There are two primary plasma proteins that bind drug molecules. Human Serum Albumin (HSA) & Alpha 1 acid glycoprotein (AGP).  The largest single component of this is human serum albumin (HSA) ~ 60% of all plasma proteins.  HSA has multiple binding sites (at least 6 primary binding sites)  Drugs must be unbound to move between plasma and tissues (binding sites) Protein Binding Continued  HSA has a preference for organic acids (carboxylic acids & phenols) but can bind many other molecules.  AGP prefers basic molecules (amines).  Molecules bound to a plasma protein are unavailable for binding to a pharmacological target. Unable to leave the plasma.  Binding to plasma proteins can affect the PK of a drug and its exposure to the desired target. Important factors are extent of binding Kd & rate of association and dissociation  Retain drug in plasma compartment  Restrict distribution of drug to into target tissue  Limit brain penetration  Require higher loading dose, lower maintenance dose Determinants of passive diffusion Drug permeability A. Drug related 1. Lipid solubility of the drug 2. pK of the drug 3. Size of the drug B. Non-drug related 1. pH of medium2. Concentration gradient 3. Surface Area 4. Temperature 5. Thickness Fick’s Law J = -D x A  C/ x Diffusion is always from higher [C] to lower [C] D = diffusion coefficient (area/unit time) At equilibrium,  C=0 Therefore, C2 = C1 Lipophilicity and Drug-Like Properties Optimal 0 < LogP < 3 Oral Bioavailability High Poor Lipid Bilayer Permeability Poor Aqueous Solubility Low -4 -3 -2 -1 0 1 2 3 4 5 6 7  Hypothetical example of how LogP can affect oral BA in a compound series. Absorption by passive diffusion permeation after oral dosing is generally considered optimal for compounds having a moderate LogP What is Lipophilicity Lipophilicity is the tendency of a compound to partition in a nonpolar lipid (fat) matrix vs. an aqueous media. Often expressed as Log P: Partition coefficient between an organic phase (octanol) and water. Log P = Log([compoundoctanol]/[compoundaq]) Log D: Distribution coefficient. Takes into account the distribution of a compound between an organic phase and an aqueous phase at a specified pH. This value can be a more useful descriptor than log P Log DpHx = Log([compoundoctanol]/[compoundaq]) Lipophilicity is a major determent of many ADME & Toxicological properties. Effects several parameters such as permeability, solubility, & clearance. These values can be determined experimentally but are often theoretical values (i.e. cLogP) Permeability depends on the pH of medium and pKa of drug only the neutral form of the drug can pass through the membrane-passive diffusion H+ + A- HA Effect of pH on drug ionization The degree of ionization of a chemical is determined by the chemical’s pKa value and the pH of its environment Henderson-Hasselbach equation Acid: HA A- + H+ Ka = ([A-][H+])/([HA]) Log Ka = log[H+] + log([A-]/[HA]) Dissociation equation of an acid or bases can be expressed as: acid: pH = pK + log([A-]/[HA]) base: pH = pK + log([B]/[BH+]) pK = the pH at which 50% ionization of the drug occurs Calculation of ionization Salicylic acid (pKa = 3) is in a solution (pH = 2) pH = pK + log([A-]/[HA]) 2 = 3 + log([A-]/[HA]) 2 - 3 = log([A-]/[HA]) [A-]/[HA] = 10-1 [HA] = 10 [A-] 90% of the drug is in the form of HA, the neutral form of salicylic acid. Drug Ionization on passive diffusion Acidic: Carboxylic acids (pKa ~ 4-5) Commercial Drugs Non-ionizable 5% Acidic 20% At Physiological pH acids are primarily in the ionized form (99%) Basic 75% Basic Groups: Amines (pKa ~ 8-10) Receptor interaction & water solubility Crosses membrane Adding a Nitrogen atom (N) often helps absorption due to the partial ionization of it at both weakly acidic and alkaline conditions. (pKA ~ 6-8) 90-99% ionized at pH of 7.4 Surface area The small intestine is long (6m long) The inner surface on the intestine is folded covered with many finger-like projections called villi and microvilli greatly increase the surface area - Most drug absorption occurs in the small intestines. Microvilli (brush border) pH affects absorption of drugs Fluids pH Stomach contents 1.0 to 3.0 Jejunum 5.0 to 6.0 Ileum 8 Large intestine 8 Plasma 7.4 Cerebrospinal fluid 7.3 Urine 4.0 to 8.0 Summary of passive diffusion 1) Can not cross membranes from a lower to higher concentration 2) Increases as the partition coefficient increases 3) Only uncharged form of the drug crosses membranes 4) Increases with surface area 5) Non-saturable – increases with increasing concentration of drug Carrier mediated transport Drugs bind to a carrier protein and are carried into the cell via the carrier protein 1. Facilitated Transport 2. Active Transport Carrier mediated transport – drug examples Many penicillins are completely ionized at the pH of small intestine predict poor absorption; however, some are well absorbed Acids Penicillin - gut Mostly as unionized Bases Dopamine - gut prodrug Quinine Carrier mediated transport – drug examples Many penicillins are completely ionized at the pH of small intestine predict poor absorption; however, some are well absorbed Acids Penicillin - gut Mostly as unionized Penicillin G Bases Dopamine - gut prodrug Quinine Active Transport Active transport is the movement of molecules from LOW to HIGH concentration. Energy is required as molecules are pumped against the concentration gradient. Proteins that work as pumps are called protein pumps. Non-saturable vs. Saturable Active Transport 1) Specific- Binding site on Carrier 2) Independent of surface area 3) Proportional to the number of carriers, protein mediated 4) Competition- A molecule of similar structure can compete for binding to the carrier 5) Drug can move from [low] to [high]. Dependent on Energy (ATP). Can become saturated at high drug concentrations Absorption from the gut For drugs given orally, must consider: 1) Surface area Most drugs are absorbed in the small intestine 2) Presence or absence of food Gastric emptying - delivery of drugs to the small intestines 3) Ion trapping pH effects on acids and bases 4) Drug formulation Lipinski’s Rule- A guide to orally available drugs Lipinski was a scientist at Pfizer. He did an analysis of marketed drugs and identified certain physicochemical property characteristics correlating to oral biovailability and overall druggability. No more than 5 Hydrogen bond donors (-acids, -OH’s, 10 & 20 amines, thiols) No more than 10 hydrogen bond acceptors (All Nitrogen, Oxygen atoms) Molecular Weight < 500 daltons (< 450) Lipophilicity measurement cLogP < 5 (-0.4 to 5.6) Often referred to as the Rule of 5 Over the years this analysis has been refined but Lipinski’s rules are still often cited today in describing favorable drug-like properties