D&M Biopharmaceutics

how the chemical and physical properties of a drug, its formulation and its administration route influence the rate and extent of drug absorption. What is biopharmaceutics? Plasma concentration of a drug against the time after drug administration. The area under the curve represents What does a plasma concentration-time amount absorbed and reaching systemic curve show? What is the AUC? circulation in active form. You can identify the Cmax (maximum concentration) and Tmax (the time when concentration is at its maximum) What is the therapeutic window? The dosage range between the minimum effective therapeutic concentration, and the minimum toxic concentration. It is the range of drug concentration that provide the therapeutic response without significant adverse effects. What does a wide therapeutic window mean? The difference between the effective and toxic threshold is large so can handle variable absorption (such as any oral medication). The difference between effective and toxWhat does a narrow therapeutic window ic threshold is small, control of drug plasmean? ma level is critical. What happens to an orally administered drug for it to reach systemic circulation? Drug release Drug dissolution (in water) Drug stability Membrane permeation First pass metabolism Modified release tablets are enteric coated to prevent gastric acids in the stomach from dissolving drugs. This means What makes modified release tablets and liquid different from normal tablets? it is absorbed in the small intestine and has a slower effect. Liquids do not require drug dissolution so are quicker. 1/8 The amount of drug from a formulation that reaches the systemic circulation relWhat is absolute bioavailability (F abs)? ative to an intravenous (IV) dose (which has 100% bioavailability) How do you calculate absolute bioavailability? F = AUC oral/AUC IV or F = (AUC oral/D oral)/(AUC IV/D IV) What is relative bioavailability? If a drug cannot be administered via the IV route, the AUC from a test formulation is compared with another standard formulation of the same drug. It can assess bioequivalence between two drug products. If they are pharmaWhat can F rel (relative bioavailability) be ceutically equivalent and their bioavailused for? abilities are similar, their effects are expected to be essentially the same. How do you calculate relative bioavailability? AUC test / AUC standard - Drug dissolution rate What factors can influence bioavailabili- Permeation/absorption rate (through ty? (of an orally administered drug) the GI tract) How is the bioavailability different for Citalopram drops (16mg worth) compared to a Citalopram tablet (20mg)? For the drops, absorption is completely independent of food intake. It has a faster absorption - Tmax is 2 hours whereas it is 3 hours for the tablets. Tablets have an 80% bioavailability after ingestion, but the relative bioavailability of the drops is 25% greater than the tablet. What is dissolution? The transfer of molecules from the solid state into solution, relevant for all routes of delivery. process of mass transfer of individual molecules from a region of high concenWhat is diffusion in terms of dissolution? tration to a region of low concentration. It involves molecular motion away from the 2/8 surface of the tablet where solvation has occurred. What are examples of diffusion? Some examples include surface phenomenon (dissolution of a tablet) and absorption (must diffuse through the cells after partitioning or through the intercellular passages, it diffuses through the polymer membrane through the polymer. It may also diffuse through the solvent through solvent-filled channels). Flux (g m-2 s-1) is the amount of material (mass) through a unit cross-sectional area (A) over time (dt) What is steady state diffusive flux and how do you calculate it? What is the particulate dissolution process? J = -D x dc/dx D is the diffusion coefficient. The negative sign denotes that diffusion occurs in the direction of a decreasing concentration. The larger the concentration gradient, the greater the flux. Drug particles interact with the water (dissolution), creating diffusion layers and these diffuse away, to expose new layers of particles. Diffusion must occur so that diffusion layers do not get too big. The solvent (water) creates a solvent cavity and the solute molecule when added creates a solution. dm/dt = DA(Cs - C) / H dm/dt is the rate of dissolution of the drug. What is the Noyes-Whitney dissolution D is the diffusion coefficient of drug in equation? (modified by Nernst Brunner) solution (rate constant). A is the surface area. h = thickness of diffusion layer. Cs = saturation solubility of the drug in 3/8 solution in the diffusion layer. C = concentration of the drug in GI fluids A low value of C will favour more rapid dissolution of the drug by increasing the value of (Cs - C). If Cs and C are equal, there is no dissolution occurring. If C is higher, then no dissolution is occurring as there is too much saturation (no more water molecules to interact and dissolve the drug). A can be affected by the presence of How do the parameters affect the rate of surfactants in gastric juice and bile salts. dissolution? Surface area is directly proportional to rate of dissolution. D (the diffusion coefficient) may be decreased by the presence of substances that increase the viscosity of fluids. Thickness of diffusion layer is inversely proportional to rate of dissolution. Cs is directly proportional to rate of dissolution. - Surface area/particle size (the smaller the particle, the greater the effective surface area exhibited by a given mass of drug and the faster the dissolution rate). What factors can affect the rate of disso- Solubility of the drug in water lution? Physiological factors - Volume of fluid in stomach - pH Drugs must cross the epithelium (by pasWhy is permeation important and what is sive diffusion). Permeability is dictated by the apical membranes (composed of it dictated by? lipids and proteins). Paracellular - between cells (if it is small enough) - Passive diffusion Transcellular - through cells 4/8 - Passive diffusion What are the ways drugs can cross the - Endocytic process - transcytosis (drug epithelium? is engulfed into cell) - Carrier mediated transport Paracellular passive diffusion depends on molecular size. What does paracellular and transcellular Transcellular passive diffusion depends passive diffusion depend on? on lipid solubility and degree of ionisation. Majority of drugs are transported across membranes by passive diffusion. All lipophilic, unionised, small molecules are easily absorbed. All hydrophilic, ionised, large molecules are not easily absorbed. What main route do most drugs take and However, this is not always the case, as what other routes can they take if not the not all drugs are transported by passive main route? diffusion. The ratio of protein to lipid in the plasma membrane (by mass) is 3:1. Small molecules can go any route, but large molecules are unlikely to passively diffuse transcellularly, receptor binding is important for active routes. Transcellular for small, lipophilic moleWhat drugs can be transported by pas- cules (due to the large surface area) sive diffusion? Paracellular for small, hydrophilic molecules Suitable for larger molecules but requires What drugs are transported by carrireceptor binding. Absorbing large hyer-mediated transport and transcytosis? drophilic molecules is difficult. What are the steps of passive drug transport? Partition between aqueous and lipid phase Diffusion across lipid membrane Partition between lipid and aqueous blood. What factors influence drug absorption? Chemical properties - lipid solubility (depends on hydrogen bonding and pH/pKa), molecular size 5/8 Mechanism of membrane transport (passive diffusion is the major path) What drugs is the epithelium more permeable to? Lipophilic, unionised molecules - Physicochemical properties of drug (size of molecules, relative aqueous/lipid What is the rate of permeation depen- solubility, ionic charge). dent on? - Nature of membrane - Concentration gradient across membrane Why is a balance needed of aqueous and lipid solubility? Needs to be aqueous soluble for dissolution in the aqueous environment of the GI fluid. Needs to be lipid soluble to partition into mucosal membranes. The partition coefficient reflects the ability of a drug to transfer from an aqueous phase to an oily phase, and vice versa. It is determined experimentally by shakWhat is the partition coefficient? How is ing a mixture of octanol and water, with it determined experimentally? a drug dissolved in whichever phase it is soluble in. After settling, samples are taken from each phase and the drug concentration is quantified (by UV, or HPLC) log ([drug] octanol / [drug] water) Log P > 0 means a drug is more oil (lipid) soluble What is the equation for working out Log Log P < 0 means a drug is more water P (the partition coefficient)? What do the soluble. These P values reflect the relative solvalues mean? ubilities of a molecule in immiscible solvents (e.g. oil and water at equilibrium). Log P is property specific to a particular molecule. 6/8 Unionised drugs have higher lipid solubility, so are more easily absorbed than ionised drugs. Most drugs are weak acids (aspirin) or weak bases (chlorpromazine). How does ionisation affect the perme- The extent of ionisation depends on pH. ation of a drug? What determines extent Absorption enhanced when pH favours of ionisation? formation of unionised drug. - If the pH > pKa for an acid, it becomes ionised. It is the opposite for a base, it becomes unionised. Aspirin's pKa (3) is higher than the stomach pH (1.2) which means it favours AH rather than its dissociation (into a conjugate base and hydrogen ion). This means it stays unionised and can be When is aspirin more likely to be more absorbed in the stomach, as unionised absorbed? drugs have higher lipid solubility. However, in the intestines, as the pKa is lower than the pH (7.4), it favours the ionised form (charged) so cannot pass through the lipid bilayer. Chlorpromazine's pKa (5) is higher than the stomach pH (1.2) which means it favours the base's conjugate acid (BH+). This is ionised so has a lower lipid solWhen is chlorpromazine more likely to ubility and it is unlikely it will be abbe absorbed? sorbed in the stomach. However, in the intestines, the pKa is lower than the pH (7.4) so favours the base, which is unionised. Weak acids are also well absorbed in the intestine (pH at surface of intestine What is the limitation of the pH-partition mucosa is 5.3 and there is a very large hypothesis? surface area). It also depends on extent of lipid solubility and certain drugs are well absorbed at all GI pH values even 7/8 if they are ionised (like tetracyclines). Some drugs like aspirin can be absorbed in the intestine when they are enteric coated. - Transcellular passive diffusion is major route. - Not too many hydrogen bonds as this What are the chemical requirements for limits absorption. absorption? - Cannot be too large molecules. - Drugs need to be able to partition into the oily cell membrane. What is Lipinski's rule of 5? - No more than 5 hydrogen-bond donors (N or O with 1 or more H) - No more than 10 hydrogen bond acceptors (N or O) - Mw (molecular weight) less than 500 Daltons - Log P (octanol-water partition coefficient) less than 5. A framework for classifying drugs based on their aqueous solubility and intestinal permeability. This knowledge informs dosage form design. What is the Biopharmaceutics ClassifiHigh solubility is the highest strength solcation System? uble in 250ml or less of aqueous media over pH range 1.0-6.8. High permeability is when 85% or more of the administered dose based on mass balance and GI stability determination permeates. 8/8