1. SESSION ONE OF TIP PROJECT Oral Delivery of Drugs 1 TIP 2009 GEPHART

2. Advantages of taking oral drugs Convenient (storage, portability, pre- measured dose) economical non-invasive, often safer route requires no special training like IV drugs or subcutaneous drugs require. Many are also available over-the- counter 2 TIP 2009 GEPHART

3. Disadvantages of taking oral drugs Drug delivery is often erratic and incomplete It is highly dependent upon patient compliance There are increased sources of drug-drug and drug-nutrient toxins Many drugs degrade in GI environment Exposes drugs to first-pass effect 3 TIP 2009 GEPHART

4. Oral administration The action of a drug is dependent upon it reaching its site of action whereby it delivers an effective response for therapeutic action. The important processes involved in the pharmacokinetic phase of drug action are:  Absorption of the drug  Distribution of the drug  Metabolism of the drug  Elimination of the drug 4 TIP 2009 GEPHART

5. Absorption of the drug Most orally administered drugs are absorbed through the membranes of the GI tract. The rate of absorption will depend upon the following:  the rate of dissolution of the solid (pill) into a solution  the pH of the medium containing the drug  the lipid-aqueous medium partition coefficient of the drug  the surface area of the absorbing region of the GI tract. 5 TIP 2009 GEPHART

6. Rate of dissolution of the solid into solution When a drug is administered orally via tablet, capsule, or suspension, the rate of absorption often is controlled by how fast the drug particles dissolve in the fluid at the site of administration. Hence, the dissolution rate often is the rate-limiting (slowest) step in the following sequence: Solid Drug dissolution Step 1 Drug in solution Absorption Step 2 Drug in Systemic circulation 6 TIP 2009 GEPHART

7. Rate of dissolution of the solid into solution continued Factors controlling dissolution, such as solubility, ionization, or surface area, will then control the overall dissolution process. dC/dt = dissolution rate D is the coefficient of the dissolving material of the drug h is the thickness of the diffusion layer surrounding the dissolving solid particles S is the surface area of the dissolution solid the drug concentration in the diffusion layer is equal to C s 7 TIP 2009 GEPHART

8. pH of the medium containing the drug Solubility is another factor determining the rate of dissolution. Salts of weak acids and weak bases generally have much higher aqueous solubility than the free acid or base; therefore, if the drug can be given as a salt, the solubility can be increased, and should have improved dissolution. For weak acids:For weak bases: The dissolution rate of weak bases will decrease with increasing pH and the dissolution rate of weak acids decreases with increasing hydrogen ion concentration. 8 TIP 2009 GEPHART

9. 9 Please go to the following: http://www.icp.org.nz/html/ph.htm to complete the activity http://www.icp.org.nz/html/ph.htm The pH of a particular drug has an effect on the movement of a drug through a membrane. It also has an effect on the dissolution of the drug into the solvent it is placed in. Please go to the link to the right to complete this activity. TIP 2009 GEPHART

10. Lipid-aqueous medium partition coefficient of the drug A drug has to pass through a number of biological membranes in order to reach its site of action. Organic medium/aqueous system partition coefficients were the obvious parameters to use as a measure of the ease of movement of the drug through these membranes. The n-octanol- water system is frequently chosen because it appears to be a good mimic of lipid polarity and has an extensive database. 10 TIP 2009 GEPHART

11. Partition coefficient Definition TIP 2009 GEPHART 11 Since the differences are usually on a very large scale, Log 10 (P) is used. The partition coefficient is the ratio of the equilibrium concentrations of a dissolved substance in a two-phase system containing two largely immiscible solvents (water and n-octanol)

12. Partition coefficient (cont.) TIP 2009 GEPHART 12 OH 1-octanol O HH water More accurate results may be obtained if the organic phase is matched to the area of biological activity being studied. n-octanol usually gives the most consistent results for drugs absorbed in the GI tract while less polar solvents give more consistent correlations for drugs crossing the blood- brain barrier. More polar substances give more consistent values for buccal absorption (soft tissues in the mouth).

13. Surface Area The surface area per gram (or per dose) of a solid drug can be changed by altering the particle size Generally, as the surface area increases, the drug will dissolve more rapidly. Therefore, many poorly soluble and slowly dissolving drugs currently are marketed in a micronized or microcrystalline form 13 TIP 2009 GEPHART

14. Drug absorption and permeation Lipinski Rule of Five The Lipinski ‘rule of 5’ was derived by an analysis of the key properties of 2,245 drug molecules believed to have entered Phase II clinical trials. States that compounds are likely to have good absorption and permeation in biological systems and are more likely to be successful drug candidates if they follow the rule of “five.” 14 TIP 2009 GEPHART

15. Lipinski Rule of Five  Five or fewer hydrogen-bond donors  Ten or fewer hydrogen-bond acceptors  H-bond donors are expressed as the sum of OH’s and NH’s and H-bond acceptors as the sum of O’s and N’s.  Molecular weight less than or equal to 500  Calculated logP less than or equal to 5  Compound classes that are substrates for biological transporters are exceptions to the rule. 15 TIP 2009 GEPHART

16. Drug absorption Drugs absorbed from the GI tract must pass through the GI tract membrane, liver, and other organs in order to reach the general circulation system. The physiology of drug absorption from the GI tract has a direct effect on the bioavailability (F) of a drug. 16 TIP 2009 GEPHART

17. 17 Please complete the activity at: http://www.icp.org.nz/html/oral_availablity.html http://www.icp.org.nz/html/oral_availablity.html The oral availability of a drug can be compared by examining the drug absorption and the first pass metabolism of the drug. The activity provided here will give you the opportunity to examine the conditions under which the drug will reach the blood stream. Please complete all activities provided. TIP 2009 GEPHART

18. Area under the curve Since the area under the plasma concentration-time curve (AUC) for a drug is a measure of the total amount of drug reaching the general circulatory system, the bioavailability of a drug may also be defined in terms of the AUC as: F = AUC/dose Or absolute bioavailability is: F = AUC po /AUC iv 18 TIP 2009 GEPHART

19. Absorption and elimination TIP 2009 GEPHART 19 The increase in plasma concentration occurs as a drug is absorbed. It is accompanied by elimination, which starts from the instant the drug is absorbed. The rate of elimination increases as the concentration of the drug in the plasma increases to the maximum absorbed dose. Figure 1: graph of the concentration vs. time of a drug that is intravenously administered (red arrow) and one that is orally administered (blue arrow). (Lemke, Williams, Roche, & Zito, 2008)

20. 20 Please go to: http://www.icp.org.nz/html/drug_clearance_1.html to complete the above activity http://www.icp.org.nz/html/drug_clearance_1.html The plasma concentration (Cp) is directly proportional to the dose rate, and inversely proportional to the clearance. As you complete this activity, examine the relationship between the plasma concentration, the dose rate, and the clearance. TIP 2009 GEPHART

21. Compartmental concepts TIP 2009 GEPHART 21 The most commonly employed approach to pharmacokinetic characterization of a drug is to depict the body as a system of compartments, even though these compartments often do not have any apparent physiologic reality. The one-compartment model considers the body as a single homogenous unit (central compartment). This simplest model is particularly useful for pharmacokinetic analysis of plasma concentration vs. time for drugs that are very rapidly distributed in the body. The two-compartments model consists of a central component, which includes the plasma and other highly perfused organs, connected to a peripheral or tissue compartment. Each compartment can be considered to include a group of tissues, fluids, or parts of organs. (Lemke, Williams, Roche, & Zito, 2008)

22. One and Two compartment models TIP 2009 GEPHART 22 Figure 2: Schematic representation of the one-compartment (I) and the two-compartment (II) models commonly used in pharmacokinetics. Arrows represent transfer of a drug because of the first-order process. C, central compartment (plasma, highly perfused organs); P, peripheral (tissue) compartment. (Lemke, Williams, Roche, & Zito, 2008)

23. 23 Please click below to complete above activity: http://www.icp.org.nz/html/volume_of_distribution.html http://www.icp.org.nz/html/volume_of_distribution.html The compartment models illustrated show the volume of distribution of drugs dependent upon their properties. Please complete all sections of this activity. TIP 2009 GEPHART

24. 24 Half-life The amount of time it takes the concentration of a drug to fall to half its original value is known as its biological half-life (t 1/2 ). For drugs that exhibit first order elimination kinetics t 1/2 = 0.693/k el TIP 2009 GEPHART

25. 25 Please click below to complete above activity: http://www.icp.org.nz/html/half_life.html http://www.icp.org.nz/html/half_life.html The half-life of a drug is the time it takes for the concentration to halve. Examine the activity here and look at the relationship between the concentration, volume delivered and the t-1/2 value. TIP 2009 GEPHART

26. Volume of distribution relationships to dosing TIP 2009 GEPHART 26 ( Lemke, Williams, Roche, & Zito, 2008)

27. Therapeutic effects and dosing of oral medications TIP 2009 GEPHART 27 When a single dose of a drug is administered orally, its plasma concentration increases to a maximum value (C max ) at t max before falling with time.’ The change in plasma concentration-time curve for a single oral dose shows the time (t lag ) for the drug to reach its therapeutic window concentration, the t max, and the C max. All of these measurements are useful in determining the correct dosage form for a drug and also the selection of analogues for development.

28. TIP 2009 GEPHART 28 Oral Dosing Minimum toxic concentration Minimum effective concentration Click here for video

29. 29 Please click below to complete above activity : http://www.icp.org.nz/html/dose.html http://www.icp.org.nz/html/dose.html Dosing: Single dose oral drugs can be compared to multiple dosing. Loading helps to bring the initial concentrations up to an effective concentration more quickly. Compare the different types of dosing within the activity provided. Compare the therapeutic windows of each trial. TIP 2009 GEPHART

30. Conclusion TIP 2009 GEPHART 30 The therapeutic effect of oral drugs depends upon the absorption, distribution, metabolism, and elimination of the drug within the body system. The absorption and distribution of a drug can be influenced by the particle size, pH, partition coefficient, and the molecular weight of the drug. The rate of absorption and elimination affect the therapeutic levels that can be achieved within the body. Dosing of a drug is dependent upon the rate of absorption and the rate of elimination. The kinetics of these processes help to determine the frequency and dosage form of the drug.

31. References TIP 2009 GEPHART 31 Lemke, T. L., Williams, D. A., Roche, V. F., & Zito, S. W. (2008). Foye's Principles of Medicinal Chemistry. Philadelphia: Wolters Kluwer. Lipinski's Rule of Five. (1997). Retrieved February 12, 2009, from Group Seminar Lipinski Rule of Five: bioinfo3d.cs.tau.ac.il/Education/CS01a/GroupSeminar/Lip inskiRuleOfFive.ppt Thomas, G. (2003). Fundamentals of Medicinal Chemistry. West Sussex, England: Wiley.