ADME Processes - Drug Absorption

Introduction and Definitions

Pharmacology is the study of how chemical substances interact with living

systems.
If substances have medicinal properties, they are considered
pharmaceuticals.
The field of pharmacology includes drug composition and properties,
interaction, toxicology, and therapy.
Toxicology is the study of the adverse effects of chemicals on living
organisms.
Toxicology is the study of symptoms, mechanisms, treatments and detection
of poisoning, specially the poisoning of people.
Introduction and Definitions

Introduction and Definitions

 Drug Absorption
Drug Distribution
Drug Metabolism
Drug Excretion
Pharmacokinetics (PK)
Pharmacodynamics (PD)

ADME Processes = Absorption + Disposition

Disposition = Distribution + Elimination
Elimination = Metabolism + Excretion

Absorption - Where/How is the drug absorbed (through the skin, the

intestine, the oral mucosa)?

Distribution - How is the drug spread through the human body?

Metabolism - Is the drug converted chemically inside the body, and into
which substances. Are these active? Could they be toxic?

Excretion - How is the drug eliminated (through bile, urine, breath)?

Complex picture of drug interactions in the body. This slide gives an idea
of the complexity of drug disposition. Shown in this slide are many of the
steps to getting drug from one site in the body to another. Many of these
processes are enzyme induced.

General Definition of Drug Absorption Passage of drug substance

molecules from the site of administration into blood circulation.
All Routes of Administration (RoAs), except for Intravascular ones, e.g. IV,
IA, etc. (i.e. Extravascular RoAs), will require a drug absorption process
through biological membranes into the blood stream (systemic circulation).
Oral RoA is the most common one because the most convenient.
On the other hand, this RoA is the most problematic one for absorption
because it offers a high variability in absorption caused by a bigger number of
factors involved in comparison with other RoAs.
The focus of the lecture will therefore be mainly on Drug Absorption after
Oral Administration of Solid Dosage Forms, but the principles applied here
can be extended on and are valid for absorption from other oral PDFs and
other RoAs.
Definition of Drug Absorption from GIT

For an effective drug therapy through oral administration, drug absorption

should be rapid and complete because this produces:

High drug level in plasma therefore a strong pharmacological effect;

Rapid onset of pharmacological effect;
Higher uniformity and reproducibility of pharmacological effect;
Lower possibility of drug interaction with GIT components and drug
degradation;
Lower frequency and severity of GIT side effects.

Factors and Steps in Drug Absorption

with its biological environment of the site of administration;

Drug substance in its dosage form formulation.

Drug absorption after oral administration of solid dosage forms will go through a
multiple step process including;
Dosage Form Disintegration
Drug release from dosage form
Drug Substance Dissolution
Drug Substance Absorption Drug passage through membrane
Main Rate - Limiting Steps
Dissolution
Absorption
 Multiple-step process of drug transfer from SDF to
BC

SDF - Solid Dosage Form; BC Blood Circulation; Dissolution Rate: a << b << c

Drug Release & Absorption involve several Unit Physicochemical Processes:

Wetting (tablet) Wetting (API particles)

Spreading Dissolution
Penetration Dissociation
Disintegration Diffusion
Deaggregation Penetration/Permeation

All except the last one are processes involved in drug release from a SDF in GIT
fluids before absorption. A drug cannot be absorbed across the GIT wall as a
solid. It must first dissolve in the fluids of the GI tract. The real drug absorption
process the drug passage from the GIT lumen into the BC.
Factors Affecting Rate & Extent of Drug Absorption from
GIT

Human (Patient) Factors

Biological (Biological Membrane)

Anatomo-Physiological (RoA)

Drug Product (API + Pharmaceutical Dosage Form) Factors

Physicochemical (Drug Substance)

Pharmaceutical (Formulation)

Human (Patient) Factors in Drug Absorption from GIT

Biological (GIT Membrane) Factors

Biological and biochemical characteristics of absorptive membrane
Molecular structure;
Physicochemical properties;
Transport mechanisms.

AnatomoPhysiological (RoA) Factors

Anatomy of RoA and Absorption Site;
Physiology of RoA and Absorption Site;
Pathologies.
 Biological & Biochemical Characteristics of Absorptive
Membrane
Absorption of drugs through biological membranes

For drug absorption into the cell, a drug must traverse the biological
membranes: stomach, intestines, lungs, skin.

Transcellular drug absorption is the process of a drug movement across a

cell.

Some polar molecules may not be able to traverse the cell membrane, but
instead, go through gaps or tight junctions between cells, a process known as
Paracellular drug absorption.

Transmembrane movement of drugs

The lipid bilayer theory
The cell membrane is composed of two layers of phospholipids between two
surface layers of proteins.
The theory explains the observation that lipid-soluble drugs tend to penetrate
cell membranes more easily than polar molecules.

The fluid mosaic model

The cell membrane consists of globular proteins embedded in a dynamic lipid
bilayer matrix. These proteins provide a pathway for the selective transfer of
certain polar molecules and charged ions through lipid barrier.
The model explains the transcellular diffusion of polar molecules.
Mechanisms of drug absorption

Passive diffusion
Carrier-Mediated Transport
1. Active Transport
2. Facilitated Diffusion
Vesicular Transport
1. Pinocytosis
2. Phagocytosis
Pore Transport
Ion Pair Formation
 Mechanisms of drug absorption

Passive Diffusion
Passive diffusion is the process by which drug molecules spontaneously
diffuse from a region of higher concentration to a region of lower
concentration; therefore from GIT lumen to blood circulation through lipidic
membrane.

This process is passive because no external energy is expended.

Passive diffusion is the major absorption process for most drugs.

The driving force for passive diffusion is due to higher drug concentration on
the mucosal side over the blood.
Carrier Mediated Transport
If the drug has a low MW and is lipophilic, the lipid cell membrane is not a
barrier to drug diffusion and absorption. Otherwise drug has to be carried by:

Active transport
Facilitated diffusion

Active transport
Active transport is a carrier-mediated trans-membrane process that plays an
important part in GI absorption of many drugs.
Active transport is characterized by the transport of drug against concentration
gradient. Therefore, this is an energy-consuming system.

This process requires a carrier that binds the drug to form a carrier-drug
complex that shuttles the drug across the membrane and then dissociates the
drug on the other side of the membrane.
 Characteristics Features of the Active
Transport
Limited number/amount of carrier molecules,
Saturability,
Specific localization within GIT (absorption window),
Structural specificity towards the substrate,
Competition for the carriers.
Comparison of Active and Passive
Transports
(in terms of Absorption Rate)

Rates of drug absorption of by passive diffusion

(line A) and by a carrier-mediated system (line
B).

Facilitated Diffusion
Facilitated diffusion is also a carrier-mediated transport system, differing from
active transport in that the drug moves along concentration gradient.
Therefore this system does not require energy input.
In terms of drug absorption, facilitated diffusion seems to play a minor role.
Example: Cephalexin (antibacterial).

Vesicular Transport
Vesicular transport (in the form of endocytosis and exocytosis) is the process
of engulfing particles or dissolved materials by the cell.
Endocytosis involves either phagocytosis or pinocytosis which are forms of
vesicular transport that differ by the type of material ingested.
This process becomes important in case of absorption of macromolecules,
e.g. proteins.
Ion Pair Formation
When the ionized drug is linked up with an oppositely charged ion, an ion pair is
formed in which the overall charge is neutral. This neutral drug complex diffuses
more easily across the membrane.
Example: Propranolol, a basic drug that forms an ion pair with oleic acid.

Pore Transport
Transport proteins form open channels across the lipid membrane of the cell.
Small molecules including drugs move through the channel by diffusion.
Pore transport can explain renal excretion and uptake of drugs into the liver.
high drug concentration to a region of low drug concentration. Rate of drug
diffusion is given by the following equation;

dQ D A K
CGI Cp
dt h
dQ/dt = rate of drug diffusion
D = diffusion coefficient
K = lipid/water partition coefficient of drug in biological membrane
A = surface area of membrane
h = membrane thickness
(CGI- Cp) = difference between concentrations of drug in GIT and plasma.

Because the drug distributed rapidly into large volume after entering the blood,
the concentration of drug in the blood will be quite low with respect to the
concentration at the site of drug absorption.
Once the drug enters into blood stream it is distributed all over the body into
tissues and organs including those involved in the elimination and therefore is
constantly being eliminated from the body.
So if the drug is given orally, then CGI >> Cp and so a large concentration
gradient is maintained, thus driving drug molecules into the plasma from GIT.
dQ D A K
Therefore the above formula can be written as: CGI
dt h
dQ D A K
or P CGI where P is the Permeability Coefficient.
dt h
 dQ
P CGI
dt
Passive Absorption First Order Process.
Absorption Rate proportional to drug concentration to absorption site,
GIT.
Effects of A, kO/W, h and CGI on Absorption Rate;

the rate of passive diffusion of drug.

Degree of lipid solubility of drug will influence the rate of drug absorption.
Partition coefficient, K, more lipid soluble drug will have a larger value of K.
Surface area of the membrane, A, larger surface area provided by
duodenum due to such features as villi & microvilli, will lead to rapid drug
absorption.
The thickness of the hypothetical model membrane, h, is a constant for
any particular absorption site.
The diffusion coefficient, D, is a constant for each drug and is defined as
the amount of the drug that diffuses across a membrane of a given unit
area per unit time when the concentration gradient is unity.

Anatomo - Physiological Factors in GI Drug

Absorption Anatomy, Histology, Physiology & Pathology of GIT
Anatomical & Physiological Factors to RoA & Absorption Site
Variable gastrointestinal pH
Variable absorptive SA
Presence of endogenous GIT components
Presence of food
Stomach Emptying Time/Rate
Intestinal Motility
Blood supply (perfusion)

Pathological Factors (Diseases of GIT)

 Anatomo - Physiological Factors in GI Drug Absorption
(Anatomy, Histology and Physiology of GIT)

Variable gastrointestinal pH
pH of GI fluids varies along the length of the GIT;
Stomach 1-3, intestine 5-7, and colon 7-8.
The GI pH may affect;
The chemical stability of the drug in the lumen;
Drug dissolution;
Drug absorption;

E.g.: Chemical degradation of erythromycin at acidic pH, leads to incomplete BA.

Anatomo - Physiological Factors in GI Drug Absorption

Variable absorptive capacity of the GIT
Absorptive capacity varies along the length of the GIT;
Small in stomach and colon; very high at small intestine, esp. duodenum;
Permeability of the epithelium to small ions, water-soluble organic molecules, and
drugs is greater in duodenum and jejunum (upper part of small intestine) than it in
the ileum (lower part of small intestine).
Variable absorptive capacity of GIT derives from variability in;
Absorptive surface area;
Presence of specific absorption carriers higher permeability
 Anatomo - Physiological Factors in GI Drug Absorption
Variable absorptive capacity of the GIT
The greater drug absorptive capacity of duodenum and upper jejunum
compared to lower part of small intestine, colon and stomach can be
explained by:
Variable absorptive surface area along the length of the GIT;
The surface area per unit length of absorbing membrane is very large at
duodenum as compared to other portions of intestine and quite small at
stomach and colon;
Presence of more specific carriers for transportation of substances through
GI mucosa in duodenum and jejunum compared to that present in ileum.

Anatomo - Physiological Factors in GI Drug Absorption

Presence of endogenous GIT components
Bile salts
Bile salts involved in emulsification of oils and fats in during digestion in GIT may;
Improve dissolution of poorly soluble drugs and enhancing their
absorption;
Form non-absorbable complexes with certain drugs (e.g. neomycin).
Enzymes secreted by GIT
Deactivation of drugs;
Activation of prodrugs;
Bacterial microflora
The ileum contains a larger bacterial population than duodenum and jejunum.
Bacterial population may be metabolize certain drugs reducing their efficacy.
E.g. Release of active drug (5-amino salicylic acid) for local action in inflammatory colon
disease by action of bacterial enzymes in colon on sulphasalazine (the prodrug).
 Anatomo - Physiological Factors in GI Drug Absorption
Presence of food
The presence of food in the GIT influences drug absorption, either
directly or indirectly via a range of mechanisms:
Increased viscosity of GI contents;
Slowing of gastric emptying rate or delaying of emptying time;
Alteration of pH;
Complexation of drugs with components in the diet;
Stimulation of GI secretions (enzymes, bile salts, etc.);
Competition between food components and drugs for specialized
absorption mechanisms (membrane transport carrier);
Food-induced changes in pre-systemic metabolism;
Food-induced changes in blood flow.

Influence of food in GIT Absorption

Increased viscosity of GI contents
This can lead to reduce rate of drug diffusion in solution from the lumen to the
absorbing membrane lining the GIT. Subsequently, decrease drug
bioavailability.
Alteration of gastric emptying
Food containing a high proportion of fat, tend to reduce gastric emptying and
thus delay the onset of absorption and action of certain drugs. Example:
Paracetamol.
Alteration of pH
In general, food tends to increase stomach pH. This can affect the rate of drug
dissolution and subsequent absorption.
Complexation of drugs with components in the diet
Example: Tetracycline, forms non-absorbable complexes with Ca and Fe.
Competition for specialized absorption mechanisms (between drugs and food
components).
 Influence of food in GIT Absorption
Stimulation of GI secretions
GI secretions such as bile salts (positive effect of fatty meals on griseofulvin
absorption);

Food-induced changes in presystemic metabolism

Certain foods may increase BA of drugs that are susceptible to presystemic intestinal
metabolism by interacting with metabolic process. Example: Grapefruit juice inhibits
intestinal cytochrom P450 and thus, taken with drugs that are susceptible to to this
enzyme is likely to increase its BA.

Food-induced changes in blood flow

Blood flow to the GIT and liver increases shortly after a meal, thereby increasing the
rate at which drugs are presented to the liver. Metabolism of some drugs is sensitive to
their rate of presentation to the liver: the faster the rate of presentation the larger the
fraction of drug that escapes first-pass metabolism. For this reason, food can increase
the bioavailability of some drugs that are susceptible to first-pass metabolism.

Examples of influence of food in GIT absorption

Examples of drugs with absorption reduced by presence of food
Amoxicillin, Aspirin, Tetracycline
Examples of drugs with absorption delayed by presence of food
Acetaminophen, Digoxin
Example of drugs with absorption increased by presence of food
Phenytoin
Example of drugs with absorption not affected by presence of food
Theophylline
 Anatomo-Physiological Factors in GI Drug Absorption
Stomach Emptying
Stomach Emptying Time/Rate - The faster stomach emptying rate, the
faster the rate of absorption.
Factors affecting stomach emptying time:
Content volume,
Food type; composition; Chemical osmotic pressure; concentration of
dissolved substances; pH of food,
Physical state of content: solids vs. liquid,
Temperature, Viscosity: Stomach prepares food content to normal values
of intestine conditions!
Co-administered drugs; e.g. metoclopramide,
Emotional state; Body position/physical exercise,
Stomach pathologies (hyperchlorhydria, achlorhydria, etc).

Anatomo-Physiological Factors in GI Drug Absorption

Intestinal Motility
Intestinal Motility
Mixing movements
Propelling movements (Peristalsis) Intestinal Transit Rate Intestinal
Residence/Transit Time;
The longer intestinal residence time the larger the extent of absorption!
Factors affecting motility
Food
Effects of disease (constipation, diarrhea)
Drugs (loperamide, etc.)
 Pathological factors affecting oral drug absorption

Drug absorption may be affected by any disease that causes changes in:

1. Intestinal blood flow

2. Gastrointestinal motility
3. Changing in stomach emptying time
4. Gastric pH that affect drug solubility
5. Intestinal pH that affects the extent of ionization
6. The permeability of intestinal wall
7. Digestive enzyme secretion

Drug Product Factors in Drug Absorption from GIT

Drug Product (API & Pharmaceutical Dosage Form)

Physicochemical Properties of Drug Substance

Pharmaceutical Dosage Form Formulation

 Physicochemical Properties of Drug Substance
Permeability Solubility

Permeability
KO/W partition coefficient in equilibrium conditions;
Ionization degree of the drug substance depending on pH and pKa;
Molecule Size/Molecular Weight
pH Partition Hypothesis

pH Partition Hypothesis
 Permeability
Relationship of Ionization Degree vs. pH and pKa

For weak acids

For weak bases

Solubility and Dissolution

Definitions
Solution homogenous dispersion of a substance in a dissolving medium
down to molecular level.
Solubility ability of a material/substance to be dissolved in a solvent or
liquid at a given temperature.
Dissolution process of transfer of the solid substance in solution.

o Application in Real Situation of Oral Drug Absorption

Solubility of API in GIT lumen environment in presence of excipients.
Dissolution Rate of API from the dosage form in GIT aqueous fluids.
 Factors Affecting Solubility
Ionization Degree (pKa and pH)
For a Weak Acid: if pH Solubility and Dissolution Rate
For a Weak Base: the opposite is true

Salt Forms of the Drugs

Polymorphism
Solubilization

Dissolution

Noyes-Whitney Formula Dissolution Rate

is the rate of dissolution;

S Surface area of the solid particle;

Ct Concentration of the solid in the bulk dissolution medium (at time t);
Cs Concentration of the solid in the diffusion (stagnant) layer surrounding the
solid particle (saturated layer solubility);
D Diffusion coefficient;
h Diffusion layer thickness.

If Ct << Cs (Ct 20% of Cs) Conditions

 Factors Affecting Dissolution Rate
Diffusion Coefficient, D
Viscosity Temperature

Specific Surface Area vs. Effective Surface Area, S (esp. for poorly soluble)
Wettability Surfactants

Diffusion layer thickness, h

Intensity of agitation/mixing/stirring

Concentration of the bulk solution

Dilution
Solubility (Cs) and Solubilization

Biopharmaceutics Classification System

Solubility
Permeability
Class I - High Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility
Clas Solubility Permeability Oral Dosage Form Approach Chances of
s Non-oral
Dosage Form
being
Required

1 High High Simple solid oral dosage form

2 Low High Techniques to increase surface

area like particle size reduction,
solid solution, solid dispersion
Solutions using solvents and/ or
surfactants

3 High Low Incorporate permeability

enhancers, maximize local luminal
concentration
4 Low Low Combine 2 and 3

Pharmaceutical Factors in Drug Absorption

Type of Dosage Form

Formulation (Excipients)
Manufacturing Process