2. By end of this topic..
▪ Define drug absorption and differentiate it from drug bioavailability.
▪ Describe the various factors that can affect the rate and extent of
absorption of drugs given orally as well as by other common routes.
3. What is drug absorption?
• Movement of drugs from the site of administration into the central
compartment
• May be oral, through the mucosa, transdermal, inhalational, intramuscular
or subcutaneous
• Multiple factors influence absorption which can be broadly classified into
drug factors (eg. molecular properties, solubility, etc) and site properties
(surface area, porosity, acidity, perfusion with blood etc).
•The most important step in pharmacokinetics study (ADME)
4.
5. Absorption in Small intestine
▪ The small intestine has the largest surface area for
drug absorption in the GI tract.
▪ Most drugs are absorbed primarily in the small
intestine
▪ The plicae circularis and microscopic finger-like pieces
of tissue (villi) increase the surface area by 10-fold
▪ Drug absorption in the intestine can occur by three
possible ways:
• Passive diffusion of lipophilic drugs, though the
membrane
• Passive diffusion of hydrophilic drugs, through pores
and gap junctions
• Active transport of larger molecules by transport
proteins
6. Factors affecting oral absorption
Physiology
• Gastro-intestine
anatomy and
physiology
• Gastrointestinal
transit times
• GIT pH
• Bile fluid
• Bacterial
microflora
• Lymphatic
absorption
• Intestinal drug
transporters
Physicochemical
• ionization state
• molecular
weight (MW)
• lipophilicity
• polar descriptors
• free rotatable
bonds (RB)
Biopharmaceutical
• Particle size
• Salt form
• Polymorphism
7. Drug stability in GIT
▪ Drug stability in the GIT can be influenced by extreme acidic pH and enzymes.
▪ Drugs that undergo metabolism by the enzymes cannot be given orally and
need to be administered via other routes of drug administration e.g. peptides
and protein drugs.
▪ In oral administration, drugs should be protected under unstable biological
environments including drug degradation induced by the GI tract and first-pass
liver effects after oral administration before reaching the targeted sites
▪ Example: insulin
8. Physiological factors that impact oral drug absorption
▪ Gastrointestinal transit times
o The absorption rate is determined by the residence time and absorption in each GIT
segment
o intestinal transit time is independent of the feeding conditions and the physical
composition of the intestinal contents
o human intestinal transit time is ~3 – 4 h
o large intestine - 8 – 72 h
▪ Gastro-intestine anatomy and physiology - small intestine is the major site of drug absorption in
humans
▪ GIT pH - pH at the absorption site is a critical factor in facilitating or inhibiting the dissolution
and absorption of various ionizable drug molecules.
9. The poorly water soluble antiretroviral drug saquinavir should be taken with food to allow bile
enhancement of its dissolution which then facilitates absorption.
Griseofulvin is absorbed best when it is taken with a high fat meal, such as a cheeseburger,
whole milk, or ice cream.
▪ Gastric emptying (GE) – the lower the GE rate, the longer the drug takes to reach the small
intestine.
o Factors affecting GE
❖ Drugs that can increase or delay GE such as metoclopramide ( ) , propantheline ( )
❖ Presence of foods can delay transit time
❖ High calorific content foods such as fat and carbs can slow GE
❖ Drug interactions in GIT e.g tetracycline can chelate calcium ion → retards its absorption
❖ Anger and agitation increase the rate, but depression and trauma have been suggested to
reduce GE.
10. ▪ Bile fluid - bile increases the absorption of fats and plays a pivotal role in the absorption of the
fat-soluble vitamins and steroids
▪ Bacterial microflora
o no bacterial microflora in the stomach and upper small intestine
o a large number of bacterial microflora populates the human’s distal small and large
intestines
o play a role in the metabolism of various chemicals and xenobiotics through hydrolysis,
dehydroxylation, deamidation, decarboxylation and reduction of azide groups
o Example: enzymes from colonic bacteria catalyze the reduction of sulfasalazine into 5-
aminosalicylic acid, which induces anti-inflammatory effects
▪ Lymphatic absorption - intestinal lymphatic route plays a key role in the absorption of drugs
that are highly lipophilic
11. ▪ Intestinal drug transporters
o can be classified into two major families, SLC family
(uptake) and ABC family (efflux).
o P-glycoprotein (P-gp), Breast Cancer Resistance Protein
(BCRP), Peptide transporter 1 (Pept1), Organic Anion-
Transporting Polypeptides (OATPS), Monocarboxylate
transporter 1 (MCT1)
o They mediate drug absorption, distribution, excretion
and drug–drug interaction.
12. Drug Dosage and Formulations
▪ Solid or liquid preparations; Examples include tablets, capsules, suspensions, lozenges, pills,
granules, powders, emulsions etc.
▪ General absorption; solution > suspension > capsules > tablets
▪ Disintegration
✓ the rate (amount of drug and time) at which the drug dissolves.
▪ Dissolution
✓ Physical process that occurs when a dosage form (e.g. tablet or gelatine capsule) breaks up
into smaller particles.
✓ starts as soon as the drug in the dosage form is wetted with gastrointestinal fluids
✓ governed by the properties of the drug and type of gastrointestinal fluid in contact with
the drug
13.
14. Physicochemical factors that impact oral drug absorption
▪ Ionization state, molecular weight (MW), lipophilicity, polar descriptors, and free
rotatable bonds (RB) influence bioavailability.
▪ Ionization - bases tend to have higher intestinal absorption, they are relatively less bioavailable
as compared to acids and neutrals
▪ MW - increasing the size of molecules above 400 g/mol will lead to a steady decline in
bioavailability
▪ Lipophilicity - (cLog P and cLog D pH7.4) indicate that very hydrophilic compounds have
drastically reduced intestinal absorption
15. Lipophilicity
▪ single most important physical property affecting potency, distribution and elimination of a
drug in the body.
▪ a measure of the interaction with a lipid.
▪ The lipophilicity of a molecule is expressed as a partition coefficient (Log P or π) of an n-
octanol/water system
▪ Log D is a distribution coefficient and is the effective lipophilicity at a given pH, which takes
into account the degree of ionization
optimal log D values range ~1–3 for oral drugs,
while optimal log P values range from 0 to 3
16. Log D is the appropriate descriptor for lipophilicity of
ionizable compounds because it accounts for the pH
dependence of a molecule in aqueous solution.
While log P and log D both describe the same physical
property (lipophilicity) it is critical that we understand
the differences between them and apply them
accordingly!
Log P describes lipophilicity for neutral
compounds only
17. Excipients
▪ Pharmaceutical dosage forms are made up of a combination of drug or active pharmaceutical
ingredients (APIs) and various excipients to support manufacture, administration or
absorption
▪ Best excipients must be able to fulfill the important functions, i.e., dose, stability and discharge
of active ingredient from the formulation.
▪ Physicochemical interactions between active ingredient and excipients can affect the
dissolution rate, stability, chemical nature and bioavailability of drugs and, consequently,
their therapeutic safety and efficacy.
▪ Excipient serves a specific purpose (i.e, binder, disintegrant, or pH adjustment) for the proper
performance of the dosage form.
18.
19. Specially formulated oral drugs
❑ Enteric coating
▪ Coated with a material that permits transit through the stomach to the small intestine before
the medication is released.
▪ Enteric coatings are primarily used for the purpose of:
✓ Protection of active pharmaceutical ingredients, from the acidic environment of the stomach (e.g.
enzymes and certain antibiotics).
✓ To prevent gastric distress or nausea from a drug due to irritation (e.g. sodium salicylate).
✓ For the delivery of drugs that are optimally absorbed in the small intestine to their primary
absorption site in their most concentrated form.
✓ To provide a delayed-release component for repeat action.
✓ Required for minimizing first pass metabolism of drugs.
20. ▪ Enteric polymers remain unionized (and thus, insoluble) at low pH values, and begin to dissolve
at a pH value of approximately 5.0–5.5.
▪ Materials used for enteric coatings include CAP, CAT, PVAP and HPMCP, fatty acids, waxes,
shellac, plastics and plant fibers.
21. ❑ Sustained release
Specially formulated oral drugs
▪ Sustained release allows delivery of a specific
drug at a programmed rate that leads to drug
delivery for a prolonged period of time
▪ Common ways to achieve such release rates are
the use of film coating, a sustained release
matrix or sustained release drug-loaded
granules.
22. pH and pKa: Degree of ionisation
▪ pH is a measure of the concentration of hydrogen ions in an aqueous solution.
▪ The absorption of a drug depends on its lipid solubility and inversely on its polarity
or degree of ionization.
The more the drug is in its un-ionized (unchanged) form, the more likely it is to be lipid-
soluble and transferred by passive diffusion through the membrane.
▪ Degree of ionization depends on the pH of the solution and the degree of dissociation
of the individual drug, pKa (the acid dissociation constant)
Most drugs are weakly acidic or basic substances and are thus
ionized at physiologic pH
▪ pKa: the pH at which half of the molecules are in the ionized form and one half are in the
unionized form.
23. Henderson–Hasselbalch equation
▪ For a weak acid the ionizing reaction is:
pH=pKa + log {[A−]/[HA]}
▪ For a weak base it is:
pH=pKa + log {[B]/[BH+]}
By controlling the pH of the solution and/or the pKa of the drug, you can
control the rate at which the drug is transferred
24. HA H+ + A-
BH+
H+ + B
3 4 5 6 7 8 9 10 11
pH
pH < pKa
Predominate forms:
HA and BH+
pH > pKa
Predominate forms: A- and B
pH = pKa
HA = A-
BH+ = B
▪ For acidic drugs
When pH of the environment < pKa of the drug, the drug is
protonated
▪ For basic drugs
When pH of the environment > pKa of the drug, the drug is
deprotonated
25. ▪ The total (ionized and
unionized concentration
of the drugs are different
in each compartment.
▪ Acidic drug being
concentrated at high pH
▪ Basic drug being
concentrated at low pH
pH partition theory
27. Body compartment 1 - stomach
Body compartment 2 – blood
HA
pH = 2 1 0.01
H+ + A-
HA H+ + A-
1 100
pH = 7.4
Membrane
Acidic drug - pKa = 4.5
[ UI ]
[ UI ]
[ I ]
[ I ]
Aspirin accumulation
28. Strychnine not absorbed until enters G.I. tract
1 = [ UI ]
Blood
pH = 7.4
99 = [ I ]
STRYCHNINE pKa = 9.5 (weak base)
100mg orally
Stomach
pH = 2
HB+
H+ + B
29. Drug-drug interactions
▪ Lead to changed systemic
exposure, resulting in
variations in drug response
of the co-administered
drugs.
▪ Pharmacokinetic
interactions may result in the
increase or the decrease of
plasma drug concentrations.
▪ Pharmacodynamic drug-drug
interactions can take
several forms, and can lead to
either enhanced activity
(synergism) or decreased
activity (antagonism).
30. Drug-disease interactions
▪ Sometimes, drugs that are helpful in one disease are harmful in another disorder.
▪ For example, some beta-blockers taken for heart disease or high blood pressure can worsen
asthma
▪ Drug-disease interactions can occur in any age group but are common among older people,
who tend to have more diseases
▪ People with diabetes, high or low blood pressure, an ulcer, glaucoma, an enlarged prostate,
poor bladder control, and insomnia are more likely to have a drug-disease interaction.
31. Drug-nutrient interactions
▪ Nutrients include food, beverages (including alcohol), and dietary supplements may alter the
effects of drugs the person takes.
▪ Drug-nutrient and food-drug interactions that can occur in the body.
33. Inhalation
▪ Large surface area available for drug
absorption
▪ Absorption depends on the particle
size
▪ Mainly by passive diffusion
▪ Also depends on ventilation rate
▪ Fast way to get into the body
because drug efflux transporters and
metabolizing enzymes are present in
the lung at much lower levels than
the gastrointestinal tract.
34. Sublingual and Buccal
▪ Rapidly and directly absorbed into the systemic
circulation via venous drainage to the superior vena
cava.
▪ More suitable for low to medium molecular weight
drugs
▪ Drug absorption can be affected if the gums or
mucosal membranes have open sores or areas of
inflammation → enhanced or irregular drug
absorption and, therefore, should be avoided or
used with caution.
▪ Smoking can decrease the sublingual or buccal
absorption of medications due to vasoconstriction
of the blood vessels.
35. Subcutaneous
▪ Absorption influenced by a compound's physiochemical
properties such as charge, molecular weight, hydrophilicity,
drug concentration (solubility), injection volume, ionic
strength, and pH 1
▪ 1 kDa are preferentially absorbed into blood
capillaries
▪ Molecules larger than about 16 kDa, (e.g monoclonal
antibodies) → absorbed into lymphatic capillaries
through passive diffusion
36. Intramuscular
▪ Rate of absorption governed by factors e.g
lipid/water partition coefficient, degree of
ionization, and molecular size
▪ Lipophilicity of a drug favors rapid diffusion
into the capillaries and lymphatic system
▪ Influenced by the total surface area of
muscle in contact with the injected solution ,
local blood flow and muscle activity.
▪ Hydrophilic and ionic drugs are absorbed
into blood circulation via the capillary pores
37. Intraperitoneal
▪ Primary route of absorption is into the
mesenteric vessels → portal vein and
pass through the liver.
▪ May undergo hepatic metabolism
before reaching the systemic
circulation.
▪ Compounds that are very
lipophilic will be quickly absorbed
systemically by the IP route
38. Rectal
▪ Drug absorption in the upper part of
the rectum is transported to the liver via the
portal system → first-pass metabolism,
▪ Lower rectum is transported directly to the
systemic circulation
▪ Has low enzymatic activity as compared
to other sections of the gastrointestinal
tract.
39. Transdermal
▪ When drug reaches the dermal layer, it becomes
available for systemic absorption via the dermal
microcirculation
▪ Two possible routes of drug penetration
across the intact skin: 1) transepidermal
2) transappendegeal pathways,
▪ Intra-cellular route - allows the transport of
hydrophilic or polar solutes.
▪ Inter-cellular spaces - allows diffusion of
lipophilic or non-polar solutes through
the continuous lipid matrix.
