S E S S I O N O N E O F T I P P R O J E C T

Oral Delivery of Drugs1

TIP 2009 GEPHART

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

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

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

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

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 Drugdissolution

Step 1Drug in

solution

Absorption

Step 2

Drug in

Systemic

circulation

6

TIP 2009 GEPHART

Rate of dissolution of the solid into solutioncontinued

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 Cs

7

TIP 2009 GEPHART

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

Please go to the following:http://www.icp.org.nz/html/ph.htmto complete the activity

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

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

Partition coefficient Definition

TIP 2009 GEPHART

11

.oct

water

C

CP

Since the differences are usually on a very large scale, Log10(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)

Partition coefficient (cont.)

TIP 2009 GEPHART

12

OH

1-octanol

O

H H

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).

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

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

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

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

Please complete the activity at: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

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 = AUCpo/AUCiv

18

TIP 2009 GEPHART

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

Please go to: http://www.icp.org.nz/html/drug_clearance_1.html

to complete the above activity

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

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)

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

Please click below to complete above activity: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

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 (t1/2).

For drugs that exhibit first order elimination kinetics t1/2 = 0.693/kel

TIP 2009 GEPHART

25

Please click below to complete above activity: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

Volume of distribution relationships to dosing

TIP 2009 GEPHART

26

(

Lemke, Williams, Roche, & Zito, 2008)

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 (Cmax) at tmax before falling with time.‟

The change in plasma concentration-time curve for a single oral dose shows the time (tlag) for the drug to reach its therapeutic window concentration, the tmax, and the Cmax.

All of these measurements are useful in determining the correct dosage form for a drug and also the selection of analogues for development.

TIP 2009 GEPHART 28

Oral Dosing

Minimum toxic

concentration

Minimum effective

concentration

Click here for video

29

Please click below to complete above

activity: 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

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.

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/LipinskiRuleOfFive.ppt

Thomas, G. (2003). Fundamentals of Medicinal Chemistry.West Sussex, England: Wiley.