Biopharmaceutics and Routes of Drug Administration

1. What is biophar- Biopharmaceutics examines the interrelationship of the maceutics? physical/chemical properties of the drug, the dosage form and the route of administration on the rate and extent of systemic (into the bloodstream) drug absorption Therapeutic response of a drug is dependent upon an adequate concentration of the drug being first achieved and then maintained at the site of action Biopharmaceutics is concerned with onset(time taken for action of drug to be seen), intensity (i.e. amount) and duration of a drug at its site(s) of action These are influenced by the rate at which a drug enters the body 2. Onset, intensity In biopharmaceutics we are particularly concerned with and duration of a drug liberation from dosage form and absorption drug at its site(s) of action determined by: 3. Drug administra- Enteral: tion routes - Delivered via the gastrointestinal tract Parenteral: - Any route of delivery except via the gastrointestinal tract - Often used as a means to directly administer drug into the blood circulation 4. Local effect: Local effect: the drug is applied directly to the local site of action - e.g. application of creams to the skin in eczema or eye drops in hay fever) 5. Systemic thera- treatment is targeted to conditions that affect the body py: as a whole or organ systems (e.g. the cardiovascular system) 1 / 31 e.g. treatment of diabetes, cardiovascular disease, blood disorders 6. Systemic deliv- Non- invasive ery can be invasive (parenteral) achieved by administering the drug: 7. Different Dosage Forms for Different Administration Routes 8. Enteral routes of administrations 9. Buccal and sub- Buccal ROA intended either for sustained local delivery or lingual route of rapid/enhanced systemic delivery administration Commonly a small (hard) tablet which is held in the mouth (often below the lip) to achieve a sustained release of the drug 1. Oral: Tablets, capsules, solutions, syrups, suspensions, emulsions, gels, powders, granules 2. Respiratory: Aerosols, inhalations, sprays, gases 3. Nasal: Solutions, inhalations 4. Eye: Solutions, ointments, creams 5. Ear: Solutions, suspensions, ointments, creams 6. Rectal: Suppositories, ointments, creams, powders, solutions 7. Topical: Ointments, creams, pastes, lotions, gels, solutions 8. Parenteral: Injections (solution, suspension, emulsion forms), implants Or a rapidly disintegrating drug tablet held under the tongue (sub-lingual), used for rapid/enhanced systemic absorption, eg nitroglycerin for the rapid relief of angina 2 / 31 10. Oral mucosa structure 11. Buccal OR sub- No 'first pass' effect - the liver is by-passed - therefore no lingual route of loss of drug due to first pass effect - high bioavailability Administration -Advantages: Rapid absorption - good blood supply to buccal cavity therefore rapid systemic absorption Drug stability - pH in mouth relatively neutral - around 6.5-6.9 (compared to stomach - acidic) - thus a drug may be more stable 12. Buccal OR sub- Inconvenient - holding the dose in the mouth is inconvelingual route of nient / uncomfortable (taste?) Administration Suitable only for low dose drugs Disadvantages: 13. Rectal route of administration Most common dosage forms are suppositories (solid/semi-solids) and enemas (solutions) Drug absorbed either across rectal and/or colonic mucosa (particularly if applied in a liquid dosage form) 14. Advantages of rectal route of administration By-pass liver - some of the veins draining the rectum (particularly the lower rectum) lead directly to the general circulation, thus by-passing the liver and the first-pass effect Useful - this route may be most useful for patients unable 3 / 31 to take drugs orally (e.g. due to vomiting, irritation) or with younger children 15. What are the Erratic absorption - although absorption is currently often disadvantages of incomplete and sometimes erratic it is a useful route of rectal route of administration administration Not well accepted - at least in the UK 16. Pulmonary route - Systemic or local delivery - Attractive target for systemic drug absorption because of its large surface area (approximately 140 m2 - an area of a tennis court) - 'Upside down tree' - like structure 17. Advantages of Large surface area - 80 - 140 m2 pulmonary route: Advantages Good blood supply - 100% of cardiac output Thin cells- Distance between epithelial surface and blood is: 0.5 - 1.0 mm (alveolar) - rapid absorption 30 - 40 mm (bronchi) Avoids first-pass hepatic metabolism 18. Pulmonary route Traditionally primarily employed for the treatment and for local delivery prevention of local respiratory diseases, e.g. asthma and chronic obstructive pulmonary disease (COPD). 19. Advantages of Local targeting of diseased tissue and higher local drug Pulmonary route concentration for local delivery: Lower systemic (plasma) concentrations, resulting in de4 / 31 creased systemic side effects Rapid onset of action (unlike oral dosage forms, which have to undergo gastric emptying before absorption and therapeutic response) 20. Pulmonary route The lung has also been considered as a route for the for systemic de- administration of drugs for systemic effect livery No other mucosal route of drug delivery provides the bioavailability of the pulmonary epithelium 21. Advantages of pulmonary route for systemic delivery Particularly for actives that cannot be administered via the oral route, e.g. proteins, peptides and antibodies that would be denatured by acid or enzymatic digestion in stomach Also, other advantages such as fast onset of action Target: alveolar region (thin barrier) 22. The nasal route Exploited to deliver drugs either locally (e.g. decongestants), or systemically (e.g. the 'triptans' for migraine) May be useful for drugs that are not absorbed orally Bypass hepato-gastrointestinal (GI) first-pass elimination Ease of administration Rich blood supply of the nasal mucosa means drug enters the systemic circulation more rapidly than when administered orally The process is non-invasive and rapid 23. The nose The nasal cavity has a volume of 15 to 20 cm3 and a what are he 3 re- surface area of 150 to 180 cm2 gions of cavity called? Each cavity consists of three regions: which region 5 / 31 is responsible 1) vestibules for drug absorp- 2) respiratory region, consisting of turbinates or chontion? chae, and 3) olfactory region Region responsible for Drug Absorption: Respiratory region 24. Nasal drug delivery - what cells does the nasal epithelium consist of? - what are these cells connected by - what is the function of cilia? The nasal epithelium consists of columnar cells (ciliated and non-ciliated), basal cells and goblet cells Ciliated and non-ciliated columnar cells are connected by tight junctions and are covered with microvilli (<300 microvilli per cell) The 4- to 6-¼ m-long cilia propel the mucus from the anterior to the posterior part of the nasal cavity 25. Nasal drug de- Nasal mucosa usually favours the passive diffusion of livery disadvan- drugs with a combination of: tages: - Low molecular weight (<1000Da) - Lipophilic character - Unionised state Nasal mucosa retains some enzymatic activity compared to other mucosae which can degrade the active compounds; however, the capacity for degradation is less than for other absorptive surfaces. Nasal congestion due to allergy or minor infection could affect the bioavailabilty of the product considerably. Drugs can cause local irritation. Mucociliary clearance - a self-clearing mechanism of the airways in the respiratory system to protect lungs by removing inhaled particles 6 / 31 26. Formulations for Drugs to be administered to the nasal cavity are generally Nasal Delivery: formulated as nasal drops (e.g. 'saline' drops) or nasal sprays (e.g. Beconase) Extent and site of deposition of an aerosol depends on factors such as particle diameter, charge and velocity at which it is moving. With both drops and sprays, ~40% of the administered dose is cleared rapidly within 20 min 27. Drug administration via the skin Two different cases have to be distinguished: - what is the major barrier to drug permeation via the skin? - Local delivery to selected skin layers, e.g. E.g. Ketoconazole (antimycotic) - Systemic delivery E.g. Hormones, Fentanyl (opioid-based pain killer), nicotine 28. Skin as a Barrier to Drug Absorption - explain structure of barrier Stratum corneum is a highly hydrophobic layer, composed of dead, flattened corneocytes surrounded by lipid bilayers Local delivery to skin layers may also result in systemic absorption The major barrier to drug permeation is stratum corneum - the outermost skin layer This arrangement resembles the ''brick and mortar'' structure of a wall where the dead corneocytes comprise the ''brick'' embedded in a ''mortar'' composed of multiple lipid bilayers Low permeability of the stratum corneum is the main reason only a handful of low molecular weight drugs are administered by this route Skin permeation of molecules is governed by diffusion 7 / 31 29. Pathways of Intercellular and Transcellular routes drug absorption - The intercellular route is considered to be the predomithrough the skin nant route 30. Oral route of ad- Wide variety of oral dosage forms available ministration: Dosage form swallowed and drug absorbed across the gastrointestinal tract (GIT), generally from the small intestine, although sometimes the colon and occasionally the stomach Most common (98% of all drugs) and preferred route in the UK 31. Advantages of Convenient - portable, no pain, easy to take (self-adminoral route of ad- istration), well accepted ministration: Cheap - In terms of administration - In terms of production - multi-dose formulations produced by automated machines in large quantities, and no need to sterilise (but must be hygienic), no danger of embolism (blockage) Variety of dosage forms available - including fast release tablets, capsules, enteric coated, layered tablets, slow release, suspensions, mixtures 8 / 31 32. Disadvantages of oral route of administration: Sometimes inefficient - high dose or low solubility drugs often exhibit poor availability as only part of the dose is absorbed across the intestinal membrane First-pass effect - drugs absorbed orally are transported to the general (or systemic) blood circulation via the liver, thus drugs which are extensively metabolised are generally metabolised in the liver during their journey from the GIT into the blood circulation 33. Oral route of ad- Slow - slow onset of action so not suitable for emergenministration dis- cies advantages Stability - certain drugs are destroyed by gastric acid e.g. insulin Food - food and GI motility can affect drug absorption. Absorption of tetracyclines and penicillins is slower with food, while the bioavailability of propanolol is higher after food, and griseofulvin absorption is higher after a fatty meal. Local effect - antibiotics may kill normal gut flora and thereby allow overgrowth of fungi. Thus, an antifungal agent may be co-administered with an antibiotic Unconscious patient - patient has to be able to swallow a solid dosage form, a liquid may be given by tube 34. Summary: Biopharmaceutics examines the interrelationship of the physical/chemical properties of the drug, the dosage form and the route of administration on the rate and extent of systemic (into the bloodstream) drug absorption • Systemic delivery can be achieved by administering 9 / 31 the drug through different ways, e.g. via inhalation, skin, orally, etc. • Oral administration is the most preferred way of taking drugs by patients but not always appropriate or possible 35. Site of absorp- - Few (acidic) drugs (e.g. aspirin) are absorbed in the tion after oral ad- stomach ministration: - Some drugs absorbed in colon (or large intestine) - Major site of drug absorption is small intestine - Primarily because of the large surface area and potential for a long contact time for the drug with the intestinal mucosa 36. Stomach Primary functions primaru function - Storage and mixing - Initiation of digestion (pH 1-3) - Reducing the contents of the stomach to a slurry (chyme) - Emptying the stomach contents in a controlled manner into the small intestine Stomach has a relatively small surface area so contribution to drug absorption is insignificant Exceptions: alcohol, aspirin, glucose, some weak acids 37. 10 / 31 function of smooth muscle in the stomach 38. Large intestine (colon) what are the 4 segments? what are the primary function? Smooth muscle found in stomach and small intestine that acts a valve and regulates the flow of partially digested food from the stomach to the duodenum The length of the large intestine averages 1.5m (60 inches) and is divided into 4 segments: ascending colon, transverse colon, descending colon and sigmoid colon Primary functions of the colon are: - Absorption of water and electrolytes - Storage and elimination of faecal materials - Large intestine has a fairly small surface area - despite of its large diameter - Minor site of drug absorption - exception: propranolol 39. structure of the Small intestine (SI) is the longest section of the GIT, in small intestine humans - length of 5-6m, surface area of 200-250 m2 what are the 3 regions of the S.I SI run from pyloric sphincter to ileo-caceal junction Comprised of three regions: duodenum, jejunum, ileum Structured to increase surface area over that of a cylinder of equivalent dimensions 40. 11 / 31 Cross section of Serosa - outer most layer contains connective tissue small intestine Muscularis - longitudinal and externa circular muscle, facilitates mixing and propelling of the gastric contents along small intestine (rate of 1cm/min) Submucosa - connective tissue, blood and lymph vessels Mucous membrane - includes epithelium Nature of epithelium (designed for absorption) and close proximity of blood supply important for absorption Nature of epithelium (designed for absorption) and close proximity of blood supply important for absorption 41. Specialisations to increase surface area of small intestine 1st level Convoluted spiral (circular) folds of submucosa covered by mucosa Present in humans & primates Folds approx. 8 - 10 mm high and 5 cm long More dense in jejunum than ileum Folds serve to give a 3-fold increase in luminal surface area 42. Specialisations Finger-like protrusions of mucosa to increase surface area of In humans, villi are 0.5-1 mm long and occur at a density small intestine - of 10-40 per mm2 2nd level More dense in jejunum than ileum Close proximity to blood and lymph supplies and the 12 / 31 counter current flow of blood leads to an enhanced absorptive capacity An increase in surface area of 30-fold 43. Specialisations to increase surface area of small intestine 3rd level Thousands of small extensions on each epithelial cell project into the lumen Microvilli are ~0.5-1.5µm tall and ~0.1µm in diameter separated by a 50nm channel Each microvillus has a dense bundle of actin filaments which gives it its extended shape contract - therefore move the fluid immediately in contact with the surface An INCREASE in surface area of up to 40-fold Overall total surface area of SI is ~200 m2, about the size of a tennis court and ~100 x the surface area of the body exterior 44. Small intestinal epithelium what is the function of the stem cells found at the base of the villi? Epithelium is one cell thick and composed of several cell types The crypts at the base of the villi contain stem cells that continuously divide by mitosis producing: - more stem cells - cells that migrate up the surface of the villus while differentiating into one of 4 main cell types Enterocytes (columnar epithelial), Goblet cells, Endocrine cells, Paneth 13 / 31 45. what are the functions of Paneth, endocrine, goblet and enterocytes? paneth- secrete antimicrobial peptides endocrine- secrete hormones goblet-secrete mucus enterocytes - absorptive cells 46. Epithelial cell (enterocyte) Predominant cell type is the enterocyte: Life span of cells are 2-3 days, cells die by apoptosis, endothelium being renewed every 36-72 h - Tall, thin cell - Nucleus at base - On the apical side numerous microvilli extend from the surface of the cell into the lumen - brush border membrane (BBM) - Major absorptive cell Individual epithelial cells are joined together to form epithelium by protein strands (known as junctional proteins or tight junctions) that surround the top of the cell These tight junctions serve two important properties, namely to i) preserve cell polarity (isolated cells are spherical) ii) limit paracellular permeability Channels between cells are water filled, only low molec14 / 31 ular weight molecules can pass through On the apical side of epithelial cell (i.e. side of cell in contact with luminal contents) is the brush border membrane (BBM) or microvillus membrane (MVM) Membrane on opposite side of cell is called the basement membrane (BM) 47. Epithelial membrane Both the MVM and BM contain a lot of extrinsic (peripheral) and intrinsic (integral) protein activity, digestive enzymes and transport proteins. About half the weight of the membrane is protein, although this is because the molecular weight of lipid is much smaller than protein, the number of lipid molecules is much greater. 48. Composition of • Complex mixture of components the gastrointesti- • Made up of saliva, gastric secretions, dietary food and nal fluid liquid • Composition changes as the fluid is mixed and delivered to the duodenum 49. Major components important for drug disposition include: - hydrogen ion concentration - affects the pH and thus the dissolution of ionisable drugs - bile salts - can combine with lipids to form mixed micelles, enhancing the solubility of some drugs - lipase - may affect drug release from lipid-based dosage forms - protein-digesting enzyme pepsin - interferes with the stability of proteins and peptides 15 / 31 50. Steps involved in the release and absorption of a drug from a tablet - Intake - Drug particles undergo dissolution - Travel and are in transit where they are absorbed - Outflow of particles 51. What dictates drug absorption? 1. Drug factors 2. Physiological/anat omical factors 3. Disease factors 52. Drug and patient factors that may influence drug absorption 53. Gastric emptying • Gastric emptying is a simple exponential or square-root function of the volume of a meal • Stomach empties liquids faster than solids • Food therefore affects not only pH but also transit • Rate of transfer is controlled by the activity of receptors • Formulation of a drug may influence drug absorption through an indirect effect on gastric emptying 54. Intestinal transit Intestinal transit time is independent of the feeding contime ditions and the physical composition of the intestinal contents The human intestinal transit time is ~3 - 4 h 16 / 31 Studies suggest that in human small intestine, there is a gradient of velocity whereby the small intestinal transit in the proximal intestine is faster compared with the distal intestine The transit time in human large intestine can vary in the range of 8 - 72 h 55. Bacterial miA large number of bacterial microflora populates the hucroflora & oral man's distal small and large intestines drug absorption Dynamic ecosystem formed by a pool of 400 -1000 adherent and non -adherent bacterial species There is no bacterial microflora in the stomach and upper small intestine - mainly because of the low pH of the human gastric content 56. Gut bacterial mi- Bacterial microflora plays a role in the metabolism of varcroflora ious chemicals and xenobiotics through hydrolysis, dihydroxylation, deamidation, decarboxylation and reduction of azide groups It has been suggested back in 1973* that the potential of the GI microbiota to metabolise foreign compounds was at least as great as that of the liver More than 40 drug substrates have since been identified for the GI microbiota The rate and extent of bacterial metabolism is influenced by the amounts of xenobiotics reaching the distal gut, where bacteria concentration is maximal 'Pharmacomicrobiomics' is a new term used to denote the effect of microbiome variations on drug disposition and response 57. Gastric physiology summary: 17 / 31 58. pH partition hypothesis 59. outline the aspH partition hypothesis only applies to drugs absorbed by suptions of the passive diffusion via the transcellular route pH partition theory Hypothesis treats intestine as a single lipid layer - separating two aqueous phases (lumen and blood) - Cell membrane not treated as a lipid bilayer Molecules cross the intestinal membrane passively (ie via the transcellular route) - log P important Only unionised molecules cross the intestinal membrane - pKa of molecule and pH of environment important Molecules pass the membrane at a rate proportional to their lipid solubility 60. pH - brief notes Need to know if the drug is ionised therefore Henderson-Hasselbalch equation relates the ionisation of a compound to the pH of the surrounding medium 61. Example: What is Unionised specie of a drug is more likely to be absorbed the degree of ion- by passive diffusion as it is more lipid soluble, via the lipid isation of a week- membrane ly acidic drug (pKa = 3.5) that is exposed to stomach pH of 1.5 and 18 / 31 intestinal pH of 5.5? 62. For an acid A substance that can act as a proton donor. - If the pH is 2 units below pKa of a molecule, the molecule is totally unionised -If the pH is 2 units above pKa of a molecule, the molecule is totally ionised -Lower pKa, stronger Ka so stronger acid 63. For a base A substance that can act as a proton acceptor, usually a base is described by the pKa of its conjugate acid -If the pH is 2 units above pKa of a molecule, the molecule is totally unionised -If the pH is 2 units below pKa of a molecule, the molecule is totally ionised 64. where are acidic Acids unionised at low pH and basic drugs Bases unionised at high pH absorbed from? - Therefore the pH partition hypothesis predicts that: - Acidic drug absorbed from the stomach - Basic drugs absorbed from the intestine - Lowest pKa (acid) for rapid absorption is approx. 3 - Highest pKa (base) for rapid absorption is approx. 7/8 65. Summary of ef- - Acid absorbed in the stomach fect of pKa of the - Base absorbed in the intestine drug and pH of the intestinal fluid 66. 19 / 31 Two main parts to the hypothesis 67. Log P Log P gives a measure of the lipophilicity of a molecule. NB Lipophilicity does not equal hydrophobicity Measure lipophilicity by adding molecule into oil and water. A more lipid soluble molecule will be drawn to the organic phase. A more water-soluble molecule will go to the water phase. Lipophilicity is assessed by the oil-water partition coefficient of a compound - denoted as P -Organic phase generally octanol (Poct), but could be chloroform or ether 68. Usually denoted as Log P 69. Partitioning (log Amount of ionised species present depends upon pH P or D) 70. Log D Log D (or Log Papp) more widely used than log P because it takes into account the degree of ionisation of the drug at a particular pH. so need to record a pH at which the experiment is performed (D = distribution coefficient, Papp = apparent partition coefficient) 20 / 31 71. difference beBoth log p and log d measure lipid solubility of a drug but tween log p and log d is more practically useful as it takes the degree of log d ionisation and pH environment into account 72. log d equation for acids and bases Log D less than or equal to log P depending upon whether the drug is ionised at that pH or unionised 73. ideal log p A drug with a LogP between 0 and 3 is sufficiently water or lipid soluble to cross the cell membrane This is a "rule of thumb": 0 and 3 are not "cut-offs", it is just that a LogP between 0 and 3 is best placed to cross the membrane - Better for drug to have slightly more lipid solubility than water solubility with passive diffusion 74. pH partition hy- Hypothesis says that a correlation exists between rate of pothesis correla- absorption of a molecule and its log P (or log D) tion The rate of absorption increase as the log p/d increases until you reach an optimal log p/d value Then, the rate of absorption decreases At low log p/d values, the rate of absorption is slow because the molecule is LESS lipidsoluble and MORE water soluble so will not pass lipid membrane easily, and will prefer to remain in a water based environment Log10 P gives an indication of the tendency of a molecule to enter into and leave the biological membrane 21 / 31 75. Low log10 P val- Slow rate of absorption - molecule prefers to reside in ues (usually d 0) aqueous (lumen) phase 76. High log10 P val- Slow rate of absorption ues Molecule prefers to reside in membrane Although molecule readily partitions into the oily (membrane) phase it does not want to partition back out into the aqueous (blood) phase - Molecule is highly lipid soluble and poorly water soluble - Will struggle to dissolve in the water based gut environment so hard to absorb 77. Intermediate log10 P values Absorption rate is maximal - optimum balance between molecule entering membrane and leaving 78. So the hypothe- Acids unionised at low pH - absorbed from stomach sis predicts that: Bases unionised at high pH - absorbed from intestine AND... Parabolic relationship between Log P/D and the rate of drug absorption 79. However, the hy- Relationship between rate of absorption and log P seen pothesis usually after absorption from the small intestine is different from fails due to sev- that predicted at low and high values of log P eral reasons.... - If you test absorption of a drug with different log p/d values you get a sigmoidal curve rather than a parabolic curve in reality - Negative log P values and value ABOVE 3 actually are absorbed better than what was predicted by the hypothesis 22 / 31 80. At high log P Highly lipid soluble drugs use the fat absorption pathway more drug abmechanisms to be absorbed across the gastrointestinal sorbed than pre- epithelium dicted: WHY? 81. At low log P more drug absorbed than predicted: WHY? Some drugs with small molecular weight can pass between the gaps of adjacent epithelial cells .g. Paracellular transport - (applies to molecules with Mw < 270) Only at intermediate log P (~0.5-2) do the results follow the pH partition hypothesis 82. To account for the paracellular pathway Small molecules can cross the intestinal epithelium via the paracellular route due to the effect of 'solvent drag' i.e. water 'dragging' molecules across Hence, low molecular weight, water soluble drugs cross membrane as a consequence of transmucosal water flux (J) 83. water flux 84. Modification of pH partition hypothesis This equation improved the partition hypothesis as it takes into account the paracellular movement 23 / 31 85. Sieving coefficient what does it describe and what is it determined by? Sieving coefficient describes: Ability of a molecule to pass through the aqueous channels Sieving coefficient determined by: - Nature of pores - Size and physico-chemical characteristics of molecule diffusing across 86. sieving coefficent at 270D anionic vs cationic vs neutral S.C 87. anionic vs cationic vs neutral S.C graph 88. implications of S.C 24 / 31 89. other exceptions/ limitations to the pH partition hypothesis 90. Surface area of stomach: Small surface area in stomach - little absorption of weak acid drug Large surface area in small intestine - more absorption 91. Gastric emptying Gastric emptying & NOT intestinal permeation is often rate rate limiting - many factors influence emptying rate - The longer is takes for drug to be emptied out of stomach into small intestine, the longer it takes for drug to reach bloodstream 92. Dissolution rate Drug must be in solution before absorption; therefore, of dosage form dissolution rate may be rate limiting - depending upon the solubility of the drug - Highly lipid soluble drug wont easily be in solution and takes longer for dissolution to occur Note that pH requirements for dissolution are opposite to that required for membrane transfer 93. Solubility 94. ion pair Hypothesis predicts that charged particles will have LESS lipid solubility so shouldn't be absorbed by passive diffusion - Charged drugs may interact with oppositely charged 25 / 31 endogenous ions - Producing absorbable complexes with high lipid solubility as the complex is neutral - Thought to be the reason why quaternary ammonium compounds (ionised at all pH) are absorbed by interacting with negatively charged bile salts 95. Fat absorption pathways • Specialised mechanisms exist for fat absorption in the GIT • Applies to high log p value drugs • Can contribute to overall drug absorption • Applies to highly lipophilic drugs 96. GIT and first - Major role in determining how much drug reaches the pass metabolism systemic circulation - Gastric metabolism is when weak acid drugs are metabolised in the stomach rather absorbed - Some drugs exhibit a high hepatic extraction ratio beta blockers, analgesics, tricyclic antidepressants - extensively metabolised in the liver (these molecules are substrates for the liver to metabolise, so they DON'T reach the small intestine to be absorbed) - Consequently less active drug available to systemic circulation 97. Efflux mechanisms (p-glycoprotein) - If a drug is a substrate to one of these efflux pumps then, once the drug has entered the cytoplasm of the epithelial cell, it is pumped back out of the cell - Drug not absorbed so is a rate limiting step/ decreases rate of overall absorption of the drug into the systemic circulation 98. summary pt 2 Ideal log p for either acidic or basic drug should be 0-3 26 / 31 99. Biopharmaceutics Classification System (BCS) • Relates drug intestinal absorption to its physicochemical properties • Categorises drug molecules on the basis of their intestinal permeability and aqueous solubility • A prognostic tool created to facilitate oral drug product development • Extensively used by the pharmaceutical industry to predict in vivo (in animals) performance from in vitro (in labs) assays of drug products for oral administration 100. criteria for high 'Highly soluble' = when the highest strength solid oral solubility and dosage is soluble in d250 mL aqueous media over the pH high permeabili- 1.0-7.5. ty Permeability categorised according to intestinal absorption in humans or in animal and/or in vitro models capable of predicting intestinal absorption. Drugs = highly permeable when intestinal absorption e90%. Class I drugs have high absorption into the circulation; class IV drugs are least desirable in drug development oral bioavailability is low and variable - A lot of drugs taken orally can have low bioavailability but this is okay because we only need a small fraction of the dosage to reach our systemic circulation - However, the bioavailability needs to be consistent 101. Biopharmaceuti- The key idea of BCS is that in vitro methodology focusing cal on permeability and solubility (as a function of pH) may 27 / 31 Classification System (BCS) objectives qualify drug products for a waiver of in vivo bioequivalence studies. - Newly updated versions of old drugs need to match the same bioavailbility of the old drug - Class 1 and class 2 drugs are unproblematic as they have high permeability and high solubility so in vitro studies can be carried out rather than in vivo studies 102. BCS Class I: High Solubility and High Permeability Compounds belonging to this class are normally expected to dissolve quickly in gastric and intestinal fluids, and readily cross the intestinal wall through passive diffusion BCS Class I are unlikely to show bioavailability or bioequivalence issues 103. BCS Class II: By definition, poor solubility and/or slow dissolution are Poor Solubility the rate-limiting steps for oral absorption of BCS class II and High Perme- compounds ability For compounds with a very large dose-to-solubility ratio, poor solubility is likely to be the rate-limiting step for absorption. Formulations designed to overcome solubility or dissolution rate problems: 104. BCS Class III: High Solubility and Low Permeability As passive diffusion is the rate-limiting step for oral absorption of BCS class III compounds, the most effective way to improve absorption and bioavailability of this class of compounds is to increase the membrane permeability Approaches to improve permeability: 28 / 31 - Prodrugs - Permeation enhancers 105. BCS Class IV: Class IV compounds exhibit both poor solubility and poor Low Solubility permeability, and they pose tremendous challenges to and Low Perme- formulation development ability As a result, a substantial investment in dosage form development with no guarantee of success should be expected A combination of class II and class III technologies could be used to formulate class IV compounds, although the success rate is not expected to be high Use of nano, complexes or co-crystals Over 90% of the marketed drugs qualify under Class II and Class IV As many as 70% of new investigational drugs suffer from poor aqueous solubility 106. Lipinski "rule of - ONLY APPLIES FOR PASSIVE DIFFUSION five" Lipinski proposed that membrane permeability can be predicted for compounds based on physico-chemical parameters (ie no need to do any laboratory experiments) Lipinski "rule of five" states that POOR absorption or permeation is more likely when a molecule has more than one of the following: 29 / 31 107. lipinski practice 108. Absorption Why do we need experimental models? Why do we need experimental models? 1. Physicochemical models and hypotheses are unreliable predictors 2. Need to study mechanisms 3. Provide data for design of clinical trials 4. Satisfy the regulatory authorities 109. Models of Gastrointestinal Drug Absorption 110. Drug Absorption Prediction Tools 111. Epithelial Models - Used as a screening tool in the pharmaceutical industry for Prediction of for the prediction of intestinal drug absorption Drug Absorption - Observed good correlation between passive drug transport through epithelial cell monolayers and that observed across the human intestine in vivo Caco-2 is a in vitro model of the intestinal epithelial barrier Relationship between Caco-2 permeability and % human intestinal absorption: good correlation so good model to predict oral absorption of drugs - better for non-class 4 drugs 112. cell monolayer 30 / 31 113. human studies 114. summary pt3 31 / 31