Absorption of Drug Part I Biopharmaceutics and Pharmacokinetics

Absorption of Drug Part I

1. Absorption Drug absorption is defined as the process of movement of unchanged drug from the site of administration to systemic circulation. 2/14/2024

2. ABSORPTION Drug that have to enter systemic circulation can be administered by three majority ways 1. Enteral route: includes peroral i.e. gastrointestinal, sublingual/ buccal and rectal routes. 2. Parenteral Route: includes all routes of administration through or under one or more layers of skin. 3. The Topical Route: includes skin, eyes or other specific membranes. 2/14/2024

3. Gastrointestinal absorption of drugs 2/14/2024

4. Mechanism of Drug Absorption Transcellular/intracellular transport Paracellular/intercellular transport Vesicular transport 2/14/2024

5. TRANSCELLULAR/INTRACELLULAR TRANSPORT The 3 steps involved in transcellular transport of drugs are – ( i ) Permeation of GI epithelial cell membrane, a lipoidal barrier – this is the major obstacle to drug absorption. (ii) Movement across the intracellular space ( cytosol ). (iii) Permeation of the lateral or basolateral membrane- this is of secondary importance. Passive Transport Process Active Transport Process 2/14/2024

6. Passive Transport Process These transport processes do not require energy other than that of molecular motion (Brownian motion) to pass through the lipid bilayer . Passive transport processes can be further classified into following types Passive diffusion. Pore transport. Ion-pair transport. d. Facilitated- or mediated-diffusion. 2/14/2024

7. Most drugs cross biologic membranes by passive diffusion. It is defined as the difference in the drug concentration on either side of the membrane. Diffusion occurs when the drug concentration on one side of the membrane is higher than that on the other side. The process is passive because no external energy is expended. - The driving force for passive diffusion is the difference in drug concentrations on either side of the cell membrane. Passive diffusion/ non-ionic diffusion/ concentration or electrochemical gradient . 2/14/2024

8. During passive diffusion, the drug present in the aqueous solution at the absorption site partitions and dissolves in the lipid material of the membrane and finally leaves it by dissolving again in an aqueous medium, this time at the inside of the membrane. Passive diffusion is best expressed by Fick’s first law of diffusion , which states that the drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained and that the rate of diffusion is directly proportional to the concentration gradient across the membrane. 2/14/2024

9. Certain characteristics of passive diffusion can be generalized The drug moves down the concentration gradient indicating downhill transport. The process is energy-independent and non- saturable . The rate of drug transfer is directly proportional to the concentration gradient between GI fluids and the blood compartment. Greater the area and lesser the thickness of the membrane, faster the diffusion; thus, more rapid is the rate of drug absorption from the intestine than from the stomach. The process is rapid over short distances and slower over long distances. 6. Equilibrium is attained when the concentration on either side of the membrane becomes equal. 7. Drugs which can exist in both ionised and unionised forms approach equilibrium primarily by the transfer of the unionised species; the rate of transfer of unionised species is 3 to 4 times the rate for ionised drugs. 2/14/2024

10. The drug diffuses rapidly when the volume of GI fluid is low; conversely, dilution of GI fluids decreases the drug concentration in these fluids (CGIT) and lower the concentration gradient (CGIT – C). This phenomenon is, however, made use of in treating cases of oral overdose or poisoning. . Greater the membrane/water partition coefficient of drug, faster the absorption; since the membrane is lipoidal in nature, a lipophilic drug diffuses at a faster rate by solubilising in the lipid layer of the membrane. 11. The process is dependent, to a lesser extent, on the square root of the molecular size of the drug – drugs having molecular weights between 100 to 400 Daltons are effectively absorbed passively. The diffusion generally decreases with increase in the molecular weight of the compound. However, there are exceptions—for example, cyclosporin A, a peptide of molecular weight 1200, is absorbed orally much better than any other peptide. 2/14/2024

11. Ion pair formation Strong electrolyte drugs are highly ionized or charged molecules, such as quaternary nitrogen compounds. These drugs penetrate membranes poorly. When linked up with an oppositely charged ion, an ion pair is formed in which the overall charge of the pair is neutral. This neutral complex diffuses more easily across the membrane. - e.g. the formation of an ion pair for propranolol (basic drug) with oleic acid. 2/14/2024

12. PORE (CONVECTIVE) TRANSPORT: A certain type of protein called transport protein may form an open channel across the lipid membrane of the cell. Very small molecules, such as urea, water and sugars are able to rapidly cross the cell membrane through these pores. Carrier-Mediated Transport 2/14/2024

13. Facilitated Diffusion 2/14/2024

14. Active Transport Active transport is a more important process than facilitated diffusion in the absorption of nutrients and drugs 1. The drug is transported from a region of lower to one of higher concentration i.e. against the concentration gradient (in the case of ions, against an electrochemical gradient) or uphill transport, without any regard for equilibrium. 2. The process is faster than passive diffusion. Since the process is uphill, energy is required in the work done by the carrier. As the process requires expenditure of energy, it can be inhibited by metabolic poisons that interfere with energy production like fluorides, cyanide and dinitrophenol and lack of oxygen, etc. Endogenous substances that are transported actively include sodium, potassium, calcium, iron, glucose, certain amino acids and vitamins like niacin, pyridoxin and ascorbic acid. 2/14/2024

15. Drugs having structural similarity to such agents are absorbed actively, particularly the agents useful in cancer chemotherapy. Examples include absorption of 5-fluorouracil and 5-bromouracil via the pyrimidine transport system. absorption of methyldopa and levodopa via an L-amino acid transport system. absorption of ACE inhibitor enalapril via the small peptide carrier system. A good example of competitive inhibition of drug absorption via active transport is the impaired absorption of levodopa when ingested with meals rich in proteins. Active transport is also important in renal and biliary excretion of many drugs and their metabolites and secretion of certain acids out of the CNS. 2/14/2024

16. Active Transport This transport process requires energy from ATP to move drug molecules from extracellular to intracellular space. 2/14/2024

17. Active Transport Process Primary active transport Secondary active transport 2/14/2024

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19. PARACELLULAR/INTERCELLULAR TRANSPORT PARACELLULAR defined as the transport of drugs through the junctions between the GI epithelial cells. This pathway is of minor importance in drug absorption. TWO PARACELLULAR TRANSPORT MECHANISMS INVOLVED IN DRUG ABSORPTION Permeation through tight junctions of epithelial cells. It occurs through openings which are little bigger than the aqueous pores. Compounds such as insulin and cardiac glycosides are taken up this mechanism Persorption Permeation of drug through temporary openings formed by shedding of two neighbouring epithelial cells into the lumen. 2/14/2024

20. VESICULAR OR CORPUSCULAR TRANSPORT (ENDOCYTOSIS) TRANSPORT During pinocytosis or phagocytosis , the cell membrane invaginates to surround the material, and then engulfs the material into the cell. Subsequently, the cell membrane containing the material forms a vesicle or vacuole within the cell. Vesicular transport is the proposed process for the absorption of Vitamin A, D, E, and K, peptides in new born. It is the process of engulfing particles or dissolved materials by the cell. Pinocytosis and phagocytosis are forms of vesicular transport that differ by the type of material ingested. Pinocytosis : refers to the engulfment of small molecules or fluid. Phagocytosis : refers to the engulfment of larger particles or macromolecules. 2/14/2024

21. Physicochemical properties of drug Dosage form, dosage form related, pharmaceutical excipient (Pharmaco Technical Factor) 1. Drug solubility and dissolution rate 2. Particle size and effective surface area 3. Polymorphism and amorphism 4. Pseudopolymorphism (hydrates/solvates) 5. Salt form of the drug 6. Lipophilicity of the drug 7. pKa of the drug and gastrointestinal pH 8. Drug stability 9. Stereochemical nature of the drug Disintegration time (tablets/capsules) Dissolution time Manufacturing variables Pharmaceutical ingredients ( excipients / adjuvants ) Nature and type of dosage form 6. Product age and storage conditions

22. Physicochemical properties of drug Particle size and effective surface area Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system. The process by which a solid or liquid forms a homogeneous mixture with a solvent or mass transfer form solid phase to liquid phase

23. Particle size and surface area of a solid drug are inversely related to each other. Smaller the drug particle, greater the surface area. Absolute surface area Effective surface area Micronisation has in fact enabled the formulator to decrease the dose of certain drugs because of increased absorption. GRISEOFULVIN dose was reduced to half and that of SPIRONOLACTONE was decreased 20 times following micronisation . For lipophilic drugs ASPIRIN, PHENACETIN AND PHENOBARBITAL , micronisation actually results in a decrease in the effective surface area. It leads to fall in dissolution rate.

24. Particle Size Reduction The absolute surface area of hydrophobic drugs can be converted to their effective surface area by: 1. Use of surfactant as a wetting agent that - Decreases the interfacial tension, and Displaces the adsorbed air with the solvent. For example, polysorbate 80 increases the bioavailability of phenacetin by promoting its wettability . 2. Adding hydrophilic diluents such as PEG, PVP, dextrose, etc. which coat the surface of hydrophobic drug particles and render them hydrophilic.

25. Particle size reduction and subsequent increase in the surface area and dissolution rate is not advisable under following circumstances – When the drugs are unstable and degrade in solution form (penicillin G and erythromycin), When drugs produce undesirable effects (gastric irritation caused by nitrofurantoin ) When a sustained effect is desired. Reducing the particle size to a submicron to improve dissolution through solubility is possible by use of one techniques such as formation of: 1. Molecular dispersion/solid solution where the sparingly soluble drug is molecularly entrapped in the lattice of a hydrophilic agent such as cyclodextrins . 2. Solid dispersion where the drug is dispersed in a soluble carrier such as PVP, PEG, urea, etc.

26. Polymorphism and amorphism , Solvates/ Hydrates Physicochemical properties of drug

27. STABLE POLYMORPH Represents the lowest energy state, has highest melting point and least aqueous solubility . METASTABLE FORMS Represent the higher energy state, have lower melting points and higher aqueous solubilities . A is the stable polymorph B is the Metastable polymorph (more soluble) C is the unstable polymorph

28. AMORPHOUS FORM Amorphous form having no internal crystal structure . Highest energy state and can be considered as supercooled liquids. They have greater aqueous solubility than the crystalline forms [as the energy required to transfer a molecule from crystal lattice is greater than that required for non-crystalline (amorphous) Solid]. Example 1. Amorphous form of novobiocin is 10 times more soluble than the crystalline form. 2. Chloramphenicol palmitate , cortisone acetate and phenobarbital are other examples where the amorphous forms exhibit higher water solubility. Amorphous > Metastable > Stable

29. Hydrates and Solvate The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates, and the trapped solvent as solvent of crystallization. The solvates can exist in different crystalline forms called as pseudopolymorphs . This phenomenon is called as pseudopolymorphism . When the solvent in association with the drug is water, the solvate is known as a hydrate. Hydrates are most common solvate forms of drugs. The anhydrous form of a drug has greater aqueous solubility than the hydrates. The anhydrous form of theophylline and ampicillin have higher aqueous solubilities , dissolve at a faster rate and show better bioavailability in comparison to their monohydrate and trihydrate forms respectively.

30. The organic ( nonaqueous ) solvates have greater aqueous solubility than the non-solvates—for example, n- pentanol solvate of fludrocortisone and succinylsulphathiazole chloroform solvate of griseofulvin are more water-soluble than their non-solvated forms.

31. SALT FORM OF DRUG Dissolution process of a salt form of a weakly acidic drug in gastric fluid.

32. One example is the dissolution and bioavailability profiles of Benzathine and various salts. Choline and the isopropanolamine salts of theophylline dissolve 3 to 4 times more rapidly than the ethylenediamine salt and show better bioavailability. Smaller the size of the counter ion, greater the solubility of salt Bioavailability of novobiocin from its sodium salt, calcium salt and free acid form was found to be in the ratio — 50 : 25 : 1.

33. Physicochemical properties of drug 1. Drug solubility and dissolution rate 2. Particle size and effective surface area 3. Polymorphism and amorphism 4. Pseudopolymorphism (hydrates/solvates) 5. Salt form of the drug 6. Lipophilicity of the drug 7. pKa of the drug and gastrointestinal pH 8. Drug stability 9. Stereochemical nature of the drug PHARMACEUTICAL FACTOR 2/14/2024

34. Drug pKa and Lipophilicity and GI pH—pH Partition Hypothesis According to the pH-partition hypothesis, the gastrointestinal epithelia acts as a lipid barrier towards drugs which are absorbed by passive diffusion, and those that are lipid soluble will pass across the barrier. Brodie et al . “ The theory states that for drug compounds of molecular weight greater than 100, which are primarily transported across the biomembrane by passive diffusion, the process of absorption is governed by: dissociation constant ( pKa ) of the drug, lipid solubility of the unionised drug (a function of drug Ko /w) and The pH at the absorption site. 2/14/2024

35. Most drugs are weak electrolytes (weak acids or weak bases), their degree of ionisation depends upon the pH of the biological fluid. If the pH on either side on the membrane is different, then the compartment whose pH favours greater ionisation of the drug will contain greater amount of drug, and only the unionised or undissociated fraction of drug, if sufficiently lipid soluble, can permeate the membrane passively until the concentration of unionised drug on either side of the membrane becomes equal i.e. until equilibrium is attained. The above statement of the hypothesis was based on the assumptions that: The GIT is a simple lipoidal barrier to the transport of drug. Larger the fraction of unionised drug, faster the absorption. 3. Greater the lipophilicity ( Ko /w) of the unionised drug, better the absorption. 2/14/2024

36. Drug pKa and Gastrointestinal pH The lower the pKa of an acidic drug, stronger the acid i.e. greater the proportion of ionised form at a particular pH. Higher the pKa of a basic drug, stronger the base i.e. greater the proportion of ionised form at a particular pH. The knowledge of pKa of drug and pH at the absorption site (or biological fluid), the relative amount of ionised and unionised drug in solution at a particular pH and the percent of drug ionised at this pH can be determined by Henderson- Hasselbach equations: 2/14/2024

37. WEAK ACIDS WEAK BASE If there is a membrane barrier that separates the aqueous solutions of different pH such as the GIT and the plasma, then the theoretical ratio R of drug concentration on either side of the membrane can be given by equations derived by Shore et al: WEAK ACIDS WEAK BASE 2/14/2024

38. Drugs pKa p H/site of absorption Very weak acids e.g. Pentobarbital Hexobarbital >8 Unionized at all pH values; Absorbed along the entire length of GIT Moderately weak acids e.g. aspirin Ibuprofen 2.5 – 7.5 Unionized in gastric pH & ionized in intestinal pH; better absorption from stomach Stronger acids E.g. disodium Cromogylate < 2.0 Ionized at all pH values; Poorly absorbed from GIT Very weak bases e.g. T heophylline Caffeine < 5.0 Unionized at all pH values; Absorbed along entire GIT Moderately weak bases e.g. codeine 5 – 11 Ionized at gastric pH, unionized at intestinal pH; better absorption from intestine. Stronger bases e.g. Guanethidine > 11 Ionized at all pH values; Poorly absorbed from GIT 2/14/2024

39. Influence of Drug pKa and absorption 2/14/2024

40. Total aqueous solubility, ST, of an IONISABLE DRUG is an important factor in the passive absorption of drugs. It is defined as the SUM OF CONCENTRATION OF IONISED DRUG IN SOLUTION AND CONCENTRATION OF UNIONISED DRUG IN SOLUTION . The solubility of unionised form of the drug is known as the intrinsic solubility of the drug. If Sa is the intrinsic solubility of weakly acidic drugs and Sb that of weakly basic drugs, TOTAL AQUEOUS SOLUBILITY ACIDS BASE 2/14/2024

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42. Lipophilicity and Drug Absorption The degree of ionisation at a particular pH and that only the unionised drug, if sufficiently lipid soluble, is absorbed into the systemic circulation. if the drug exists in the unionised form , it will be poorly absorbed if it ha s poor lipid solubility (or low Ko /w) Systemic Circulation GASTROINTESTINAL TRACT CELL MEMBRANCE 2/14/2024

43. ACIDS BASE 2/14/2024

44. Limitations of the pH-partition hypothesis 1. Presence of virtual membrane pH 2. Absorption of ionised drug 3. Influence of GI surface area and residence time of drug 4. Presence of aqueous unstirred diffusion layer PRESENCE OF VIRTUAL MEMBRANE pH 2/14/2024

45. PRESENCE OF AQUEOUS UNSTIRRED DIFFUSION LAYER Aqueous Bulk Fluid of the GIT Aqueous Unstirred Layer Lipoidal Layer (Cell Membrane) Blood Limitations of the pH-partition hypothesis 2/14/2024

46. ABSORPTION OF IONISED DRUG INFLUENCE OF GI SURFACE AREA AND RESIDENCE TIME OF DRUG Limitations of the pH-partition hypothesis 2/14/2024

47. DRUG PERMEABILITY AND ABSORPTION M = amount of drug absorbed P eff = effective membrane permeability A = surface area available for absorption C app = Apparent Luminal Drug Concentration t res = residence time of Drug in GI lumen The three major drug characteristics that determine the passive transport or permeability of drugs across intestinal epithelium are Lipophilicity of drug expressed as log P. Polarity of drug which is measured by the number of H-bond acceptors and number of H-bond donors on the drug molecule. Molecular size. 2/14/2024

48. Dosage form, dosage form related, pharmaceutical excipient (Pharmaco Technical Factor) Disintegration time (tablets/capsules) Dissolution time Manufacturing variables Pharmaceutical ingredients ( excipients / adjuvants ) Nature and type of dosage form 6. Product age and storage conditions PHARMACEUTICAL FACTOR 2/14/2024

49. 1. Disintegration Time: Coated tablets especially sugar coated have longer DT. DT is directly proportional to the amount of binder present and the compressional force of the tablet. 2 . Manufacturing /Process variables: Manufacturing process that affects the DT are : a. Method of granulation. b. Compressional force. 2/14/2024

50. 3. Pharmaceutical ingredients: Excipients used to ensure the acceptability, physicochemical stability during the shelf life, uniformity of composition and dosage, and optimum bioavailability and functionality of the drug product. a. Vehicles b. Diluents c. Binder and granulating agents d. Disintegrants e. Lubricants f. Coating g. Suspending Agents h. Surfactants 4. Nature and type of Dosage form: As a general rule, the bioavailability of a drug from various dosage form decreases in the following order: Solution > Emulsion > Suspension > Capsules > Tablets > Coated tablets > Enteric Coated tablets > Sustained Release products. 2/14/2024

51. PATIENT RELATED FACTORS AFFECTING DRUG ABSORPTION Gastrointestinal Tract The gastrointestinal tract is a muscular tube approximately 450 m in length with varying diameters. It stretches from the mouth to the anus and consists of four main anatomical areas: the oesophagus , the stomach, the small intestine and the large intestine or colon. The majority of the gastrointestinal epithelium is covered by a layer of mucous. This is a viscoelastic translucent aqueous gel that is secreted through out the GIT, acting as a protective layer and a mechanical barrier. 2/14/2024

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53. Gastrointestinal Tract: Organs pH Membrane Blood Flow L/min Surface Area Sq M Transit Time hrs By-pass liver Buccal 6.8 to 7.00 thin Good, fast absorption with low dose small Short unless controlled yes Oesophagus 5-6 Very thick no absorption - small short, typically a few seconds, except for some coated tablets - Stomach 1.0 to 3.00 normal 0.15 small (0.1 to 0.2 ) 30 min (liquid) - 120 min (solid food) Apprx . 1 to 5 hrs no Duodenum 5 - 7 normal Good Very large very short, no 2/14/2024

54. The environment within the lumen: Gastrointestinal pH As we observed from the previous tables, the pH of fluids varies along the length of the GIT. The gastrointestinal pH may influence the absorption of drugs in a variety of ways: A- It may affect the chemical stability of the drug in the lumen e.g. penicillin G, erythromycin B- affect the drug dissolution or absorption e.g. weak electrolyte drug Luminal enzymes The primary enzyme found in gastric juice is pepsin. Lipases, amylases and proteases are secreted from the pancreas into the small intestine. Pepsins and proteases are responsible for the digestion of protein and peptide drugs in the lumen. Characteristics of GI physiology and Drug Absorption (cont.): 2/14/2024

55. The lipases may affect the release of drugs from fat / oil – containing dosage forms. Bacteria which are localized within the colonic region of the GIT secrete enzymes which are capable of a range of reactions. e.g. Sulphasalazine which is a prodrug used to target the colon. Sulphasalazine active drug (5-aminosalycylic acid) treat inflammatory bowel disease I. Characteristics of GI physiology and Drug Absorption (cont.): Bacterial enzymes 2/14/2024

56. PATIENT RELATED FACTORS I. Age II. Gastric Emptying Factors influence gastric emptying: 1. Volume of Meal 2. Composition of Meal 3. Physical State and Viscosity of Meal 4. Temperature of Meal 5. Gastrointestinal pH 6. Electrolyte and Osmotic Pressure 7. Body Posture 8. Disease State 9. Drugs III Intestinal Transit 2/14/2024

57. The time a dosage form takes to traverse the stomach is usually termed: the gastric residence time, gastric emptying time or gastric emptying rate. 2/14/2024

58. II Gastric emptying and motility: Factors Affecting Gastric Emptying 2/14/2024

59. II Gastric emptying and motility: Factors Affecting Gastric Emptying Viscosity Rate of emptying is greater for less viscous solutions Emotional states - Stressful emotional states increase stomach contraction and emptying rate - Depression reduces stomach contraction and emptying Disease states Rate of emptying is reduced in: Some diabetic patients, hypothyrodism Rate of emptying is increased in: hyperthyrodism Excercise Reduce emptying rate 2/14/2024

60. Presystemic metabolism: Definition: The metabolism of orally administered drugs by gastrointestinal and hepatic enzymes, resulting in a significant reduction of the amount of unmetabolized drug reaching the systemic circulation. Gut wall metabolism This effect is known as first-pass metabolism by the intestine. Cytochrome P450 enzyme, CYP3A, that is present in the liver and responsible for the hepatic metabolism of many drugs, is present in the intestinal mucosa and that intestinal metabolism may be important for substrates of this enzyme e.g. cyclosporin . 2/14/2024

61. Presystemic metabolism Hepatic metabolism After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs (e.g. propranolol ), sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus greatly reduces the bioavailability of the drug. 2/14/2024

62. Presystemic metabolism 2/14/2024