Factors+Affecting+Drug+Absorption

Pharmaceutics II – Okamoto: 1/13/2005 Oral Drug Absorption

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Factors Affecting Drug Absorption 

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Small Intestine – Is the major absorptive organ. o There is not much drug absorption a bsorption in the colon (mostly water) or in the stomach. There is about 27 feet of small intestine, so there is lots of time for o absorption. Drug absorption is affected by pH, solubility, and the stability of dosage o forms. Bioavailability – the amount of drug available for therapeutic purposes  how much drug is available circulating throughout the body (in plasma as a free drug). d rug). Rate Limiting Factors to Drug Absorption Bioavailability ( Often measured in the Plasma). o Sources of Incomplete Drug Absorption – Limiting Factors (4)  The Drug is not delivered from its formulation over an appropriate time frame in solution form to those sites in the GI tract where it is well absorbed (such as the small intestine). You want the drug into solution form by the end of the • small intestine.  Decomposition of the drug in the GI tract or complexation into a non-absorbable form. Decomposition – may be hydrolysis reactions (remember • from pharmaceutics I). Complexation – How smaller molecules interact with • larger molecules Such as drug interactions with proteins, or ligands o and receptors  these are regulated by noncovalent interactions. o Example: Drug molecules bind to albumin, so it is limited because it does not bind to the target, such as another receptor. Ex: Very hydrophobic drugs partition into oil o droplets  these oil droplets come from the fat in our diet, drugs will partition into fat globules and then will not be available to bind to its target (why “take on an empty stomach” is important).  Inefficient Transport across the gut wall (the apical to basolateral direction). This is often seen with ionic, ionized or hydrophilic • molecules. The drug can’t be transported if the transport system is • saturated (all the appropriate receptors are filled with drug molecules).


Efflux Pump –

Lumen

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Hydrophilic Drug

pumps drug out of the cell Drug back into the lumen

There is a physiological (efflux pump) and physical barrier (cells)

Drug

Blood 

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Drug Metabolism or Elimination en route to systemic circulation. The liver plays a large role in drug metabolism; drugs are • absorbed in the small intestine, and they enter portal circulation and go to the liver where they may be metabolized. Intestinal epithelial cells play a significant role in • metabolizing drugs. GI Tract as a Dynamic System – Affects Drug Absorption Transit time of the dosage form/drug o Appropriate time frame of release and absorption must be greater than o decomposition and complexation.  Has to do with the formulation of the tablet (for example) Disintegrant – particles of the drug (or crystals) try to get • individual drug molecules to go into solution  it is the individual drug molecules that are being absorbed. o Need Disintegration and Dissolution to occur in the GI tract so the individual drug molecules can be absorbed. Drug in systemic circulation Gut/Liver metabolism Biliary Excretion

Decomposition Drug in solution at uptake sites Complexation Absorption

Release

Transit (depends on GI motility)

Decomposition Complexation Absorption Drug in solution at uptake sites

Gut/Liver metabolism Biliary Excretion

Figure I. Steps in drug absorption and sources of incomplete bioavailability Drug in systemic circulation following oral administration of a solid dosage form.


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Biopharmaceutics Classification Scheme (BCS): - This scheme is used to Categorize all drugs taken orally  There are four classes: I – IV, this is based on Solubility and Permeability.

Table I. The Biopharmaceutics Classification Scheme Class I HIGH SOLUBILITY HIGH PERMEABILITY

Class III HIGH SOLUBILITY LOW PERMEABILITY

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Class II LOW SOLUBILITY HIGH PERMEABILITY

Class IV LOW SOLUBILITY LOW PERMEABILITY

Dissolution Testing – Determine which class the drug belongs to. o Class I – High absorption is predicted, but testing still needs to be done for rapid release.  FDA approves that if you can show that a drug fits in class I, it does not have to undergo absorption testing (which is laborious). These drugs include “me too” drugs  derivatives of • parent drugs that have already undergone testing. Toxicity testing still needs to be done. • Testing still needs to be done to verify the drug will be • released in a timely matter, ex. Griseofulvin fashion. o Class II – Limited by solubility, but has high permeability (how well a molecule moves across a barrier), so the dissolution of the drug is rate The optimal limiting (two types). situation for class  Equilibrium – lack of fluid volume for dissolution  there is not II Drugs would enough liquid in the gut for the drug to go to equilibrium. be to have a low dose / The GI tract has about 5-10L entering the lumen in a 24 • permeability hour period. ratio. Ex. Griseofulvin (not very soluble, but permeable). The • solubility is 15mcg/mL, the therapeutic dose is 500mg, and the volume of fluid needed is 33L. o The Key to delivering the therapeutic dose  the GI is a dynamic (not closed) system, so the dose can


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be delivered. The drug is absorbed out of the lumen into the blood stream, so the absorption is enhanced…

Lumen Griseofulvin = 15mcg/mL

There is an instant dilution effect; so there is a positive driving force. ≤ 3mcg/mL will not see any negative effects If the derivatives of grisiofulvin (for example) are not so permeable, then more molecules in the lumen that are not being transported…this should increase permeability because building up the concentration  so will see more with drugs that are absorbed through membrane transporters.

Blood

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Kinetic – the drug dissolves too slowly for the entire does to become dissolved before the drug has passed the absorption site (ex. Digoxin) The rate of solution (not the solubility) is the issue! • Once the Drug is in the blood, it will be carried away; so • for every molecule that goes into the blood stream, another will go into solution. Once the drug is in the blood: • It could be metabolized by the liver. o Could bind to albumin (so it is no longer free in o solution). o Can bind to its target; then it is pulled out of the blood stream. *The process of achieving the therapeutic dose of a drug is trial and error *  Class III – Need to have rapid dissolution to increase contact time. o The drugs are highly soluble, but not very permeable Ex: Ionized drugs or hydrophilic drugs  you want to increase the o dissolution time to increase the contact time so more of the drug can be absorbed.  But the longer the drug is in solution, there is an increased chance of degradation.


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The Saturated or Unstirred Layer – the drug in this layer is dissolved to the maximum.

The Rate of Dissolution slows as the concentration in the bulk solution approaches the saturated concentration  you end up with zero…which means everything is at equilibrium, so the solution is saturated. Drug Particles in the Solution 1. They are only absorbed from the surface because only part is exposed to water. 2. The thickness of the unstirred layer depends on how well the solution is being stirred. 3. The Rate of Dissolution depends of the saturating content of the drug molecule and the thickness of the unstirred layer. a. The concentration affects the amount of material getting into solution over time; how long does it take for drug molecules to go from the unstirred to the bulk solution.

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Class IV – these are compounds that are poorly absorbed, there is a negative effect of poor formulation.


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Physiochemical and Physiological Parameters Important to Drug Dissolution in the GI. Table 2. Physiochemical and Physiological Parameters Important to Drug Dissolution in the GI Tract.

Factor

Physiochemical Parameter

Physiological Parameter

Surface Area of the Drug

Particle size, wettability

Diffusivity of the drug

Molecular size

Surfactants in gastric juice and bile Viscosity of luminal contents Motility patterns and flow rate pH, buffer capacity, bile, food components Permeability

Boundary layer thickness Solubility

Hydrophilicity, crystal structure, solubilization

Amount of Drug already dissolve Volume of solvent available

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Very Important Table

Secretions, co administered fluids.

The Kinetics of drug dissolution:

dXd = A * D (Cs - Xd/V) dt δ

Xd = amount of drug in Solution A = effect of surface area of the solid drug (smaller particles have a larger surface area) D = Diffusion coefficient

δ = effective diffusion C = Xd / V 

Boundary layer thickness adj. To dissolving surface  the thickness of the unstirred layer. Cs = saturation solubility  the most amount of drug that can dissolve in the solution. V = the volume of the dissolution medium.

The Effect of Permeability: “Sink” conditions. Body Fluid Volumes o  Total – 40L  Extracellular – 15L  Intracellular – 25L How much drug is left in the “sink” (lumen)* * Highly permeable drugs  sink conditions maintained o with respect to time < 20% of the drug left in the lumen.

Pharmaceutics II – Okamoto: 1/13/2005 Oral Drug Absorption o

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Less permeable drugs  there is a buildup of drug In the lumen, therefore the dissolution rate decreases With respect to time  this negatively affects bioavailability. “SINK” CONDITIONS

10L the [ ] = .4 molecules / L

40L the [ ] = .1 molecules / L

The drug molecules go from the G.I tract  body; there is an instant dilution effect; so there is ALWAYS a [ ] gradient when you compare a molecule in the body versus the G.I tract.  Biological processes make an even larger gradient into the bloodstream…this is seen in highly permeable drugs.

Biological Parameters 

Genetic Variability o Intersubject – There are genetic differences found between two different individuals.  These genetic differences are typically found in genes that code for proteins  they are common and are called polymorphisms . Polymorphisms affect the function of the protein some  • this explains why there are ethnic differences in the capacity for people from different ethnic groups to metabolize drugs. For example, Asians vs. Caucasians  Cytochrome o p450 may be less active in the Asian population, so the bioavailability of the drug will be greater. o Other genetic variables that affect drug delivery is carrier transporters.  Polymorphisms can affect how efficiently transporters can carry the drug across epithelial cells. o G.I motility may also be different from person to person. o Intrasubject – There are differences within you.

Pharmaceutics II – Okamoto: 1/13/2005 Oral Drug Absorption 

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G.I tract conditions can change minute to minute, or within the day (circadian rhythm). Ex: when you sleep, there is not any food, so GI motility • slows  There are changes from Fed vs. fasted states Acid secretion • Enzyme secretion • G.I motility • Bile Salts/acids – the concentration is higher during a meal • that during a fasted state.  Stress can cause changes: Can lead to hyper gastric acid secretion • Motility. • Luminal Composition o pH  How does pH affect oral drug delivery? Degradation: Hydrolysis, such as acid catalyzed • hydrolysis Ionization/protonation – this affects the solubility – it • could increase or decrease the solubility At a low pH: basic drugs will be more soluble o because protonated weak acids exhibit poor solubility. But if you increase solubility, you also increase the o chance of degradation; so if the drug is not soluble in low pH, it is protected in the stomach  this helps protect against hydrolysis.  Gastric  fasted (pH is 1.4 – 2.1) vs. fed state (pH 3 – 7). The pH in the fasted state is low relative to the fed state. • A person typically returns to the fasted state from the fed • state in about 2-3 hours. During a fasted state: • There are not very many components in the o stomach, so the acid that is secreted dominates and the fluid is acidic. During a Fed State: • Much more acid is pumped out, but the food o becomes degraded and may serve as a buffer  so the buffer capacity in the fed state is higher, and so is the pH.  Hypo/achlorhydria  over the age of 65 (10 – 20%, blocker therapy. People > 65 years old have lower acid secretion naturally. • People on PPI’s don’t have any acid secretion. •

Pharmaceutics II – Okamoto: 1/13/2005 Oral Drug Absorption o

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A higher than normal pH affects the bioavailability of drugs.

Intestinal Colonic  bacterial activity can lower the pH of the colon to about 5 because of undigested carbohydrates that are being converted to short fatty acid chains. Bacteria metabolize carb’s and then excrete protons as a • byproduct which creates an acidic environment.

Table 2. pH in the Small Intestine in Healthy Humans in the Fasted and Fed States. Location

Fasted State pH

Fed State pH

4.9 6.1

5.2 5.4

Mid – Distal Duodenum More Basic

6.3 6.4 Jejunum Ileum

More Basic

4.4 – 6.5 6.6 6.5 6.8 – 8.0 7.4

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There are only minor changes in the fed vs. Fasted state this is relatively constant environment in issues related to solubility and h drol sis.

5.1 5.2 – 6.0 6.2 6.8 – 7.8 6.8 – 8.0 7.5

Buffer capacity – The capacity of a volume of liquid to resist changes in pH  the pKa of a molecule must be within certain parameters of the pH to be buffered. o Broken down food provides buffering capacity. o This is very important, because it helps to predict the affects in the solubility and degradation of drug molecules. Surfactants – this is the effect of bile salts and bile acids  they function to help emulsify the oily components in your diet…also helps emulsify the hydrophobic drugs. Two things happen with surfactants: o  They help wet the solution/particle  wetting Then the water treats the particle as a hydrophilic entity; • this reduces the surface tension of the water, so it helps the water and the particle to interact…  Facilitates the solubilization into micelles Facilitates the hydrophobic drug to get out of fatty • environment, and stays into the aqueous solution. (Remember from Pharm I  decrease interfacial tension?). Helps drug molecules diffuse through the solution to • Enterocyte, where it can then be absorbed.

Pharmaceutics II – Okamoto: 1/13/2005 Oral Drug Absorption 

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Enzymes – in particular pancreatic enzymes  which aid in the digestion of dietary products. o Proteolytic enzymes have a minute affect of drug absorption, unless the drug is a protein  the protein is broken down into amino acids, and it then can act as a buffer. Enzymes may affect complexation. o  Drugs may be bound to proteins, enzymes degrade the protein, and then the drug is released and free to be absorbed. o Drugs may be degraded by proteo enzymes if the drug looks like a protein  Ex. Insulin; you cannot pop an insulin pill  it must be injected because the insulin will be degraded in the G.I tract. o Enzymes also degrade fat  Lipases hydrolyze fat (very important!!)  If fats are rapidly hydrolyzed and absorbed, the absorption of very hydrophobic drugs may be affected.  Look at griseofulvin table to see how dietary fat affects the absorption of hydrophobic molecules.

Figure 7. This is a comparison of the effects of different types of food intake on the serum griseofulvin levels following the 1.0g oral dose  griseofulvin concentrations under different conditions.

High Fat C o n c e n t r a t i o n

Oleomargine 60g

How much of the drug shows up in the blood stream.

Oleomargine 30g

No Fat – such as Adkins diet Fasting

Time

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Volume – there is only a certain volume of liquid in the G.I tract. So there are equilibrium limited drugs o The amount of G.I fluids depend on fed (more volume) vs. fasted state. o Fluid is secreted into the lumen of the G.I tract (it is later recovered). See o graph on handout.


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Hydrodynamics in the GI Tract – o

o

o

o

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Mixing patterns: different types of motility that can change minute to minute.  Peristalsis – moving food along the G.I tract  this type of movement effects the transit time.  No activity (quiescence)  Segmental Movements  2cm…the contents of the G.I tract are squished; this facilitates absorption and dissolution.  Propagative movements (short or long range)  15cm for short  Tonic contractions Flow Rates – Transit time; how long particles stay in the G.I tract.  Small particles and water have fast transit time, while fats have a physical chemical issue  when you stand up, the fats float to the top of the surface of the stomach.  Caloric density affects the transit time. Small Intestine residence time-little difference  There is not much difference in the fed vs. fasted state: It takes several hours under normal circumstances  the transit time is regular and constant. Residence time in colon  It takes 24 hours to 3 days  there is a lot of mixing that occurs in the colon; it is not an absorptive organ. SIF – Stimulated Intestinal Fluid  Class I or II can do dissolution testing  mix salts and enzymes and buffers to approximate as closely as possible the contents in the lumen of the stomach.

Factors+Affecting+Drug+Absorption

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