Drug Absorption

• Absorption is the process by

which a drug enters the
bloodstream without being
chemically altered or
• The movement of a drug from its
site of application into the blood or
lymphatic system
Cell membrane
 Drug Absorption
• Factors which influence the rate of
absorption
– types of transport
– the physicochemical properties of the drug
– protein binding
– routes of administration
– dosage forms
– circulation at the site of absorption
– concentration of the drug
 Drug Absorption
• The rate at which a drug reaches it site
of action depends on:
– Absorption - involves the passage of
the drug from its site of
administration into the blood
– Distribution - involves the delivery of
the drug to the tissues
 Drug Absorption
• Mechanisms of solute transport
across membranes
– passive diffusion
– filtration and bulk flow
– endocytosis
– ion-pairing
– active transport

– Drug Absorption animation

 The Cell Membrane
• The cell membrane functions as a semi-permeable barrier, allowing
a very few molecules across it while fencing the majority of
organically produced chemicals inside the cell.
• The most common molecule in the model is the phospholipid, which
has a polar (hydrophilic) head and two nonpolar (hydrophobic) tails.
These phospholipids are aligned tail to tail so the nonpolar areas
form a hydrophobic region between the hydrophilic heads on the
inner and outer surfaces of the membrane. This layering is termed a
bilayer
• Cholesterol is another important component of cell membranes
embedded in the hydrophobic areas of the inner (tail-tail) region..
• Proteins are suspended in the inner layer, although the more
hydrophilic areas of these proteins "stick out" into the cells interior
as well as the outside of the cell. These integral proteins are
sometimes known as gateway proteins. Proteins also function in
cellular recognition, as binding sites for substances to be brought
into the cell, through channels that will allow materials into the cell
via a passive transport mechanism, and as gates that open and
close to facilitate active transport of large molecules.
• The outer surface of the membrane will tend to be rich in glycolipids,
which have their hydrophobic tails embedded in the hydrophobic
region of the membrane and their heads exposed outside the cell.
These, along with carbohydrates attached to the integral proteins,
are thought to function in the recognition of self
 Transport of drug
• Passive diffusion and filtration
• Specialized transport
• Carrier transport
• Facilitated diffusion
• Active Transport
• Primary
• Secondary
• Pinocytosis
 Passive diffusion

• Conc. Gradient membrane separating two body compartments,i.e higher

to lower conc.
• lipid solu in lipoidal part 0f matrix of membrane
• Does not involve a carrier, not saturable and shows low structural
specificity
• Rate of transport proportional to lipid water partition coefficient means
how readily the molecule moves between aqueous and lipid media
• Water soluble drugs penetrate through aqueous channels e.g.tight
junctions , endothelial linings of BV
• most lipophilic drugs can pass through simple diffusion
• Fick law of diffusion
• ( C1_ C2)×permeability coef
• Flux (molecules per unit time) = ---------------------------------------× area
• Thickness
• C1 = higher conc
• C2 = lower conc
• Area = area across which diffusion is
occuring
• Permeability coefficient = measure of
mobility of drug
• Thickness of path
 Filtration
• It is the passage of drugs through
• aqueous pores
• Paracellular spaces
• e.g
• capillaries in brain, glomeruli
• Increased by hydrodynamic flow occurring under
hydrostatic or osmotic pressure gradient
• Lipid insoluble drugs can cross membranes if MW less
than 100-200
• In p c spaces (40 A) most drugs even albumin can cross
• Dependant on rate of blood flow
• Active and Passive Transport
• Passive transport requires no energy from the cell.
Examples include the diffusion of oxygen and carbon
dioxide, osmosis of water, and facilitate Types of passive
transport.
• Active transport requires the cell to spend energy,
usually in the form of ATP. Examples include transport of
large molecules (non-lipid soluble) and the sodium-
potassium pump.
 Carrier Transport
• Transporter
• Proteins
ion channels
Transporter combine either substrate
Undergo conformational change
Carrying the substrate to other side of membrane
Substrate dissociates
Transporter returns to original state
Properties
Specific for substrate
Saturable
Competitively inhibited
Slower than flux through channels
Passive Transport
 Facilitated diffusion

• Solute carrier transporter ( SLC)

• No energy required
• Higher to lower conc.
• Facilitates permeation of poorly diffusible
substrate e.g. glucose in muscle and fat by
GLUT4
 Active Transport
• Requires energy
• Inhibited by metabolic poisons
• Transporters against electrochemical
gradient i.e. low to high resulting selective
accumulation on one side of membrane
• E.g. Levo dopa and methyl dopa from the
gut by aromatic amino acids , P-gp
 Primary Active Transport
• Energy obtained by hyrolysis of ATP
• Transporter belongs to ATP binding
cassettee( ABC)
• Intracellular loop has ATP ase activity
• Mediate efflux of solute from cytoplasm to
extracellular or ICL
• Transpoters
• P-gp
 Secondary transport
• Set of SLC transporter
• Energy from downhill movement of another solute ( mostly Na)
• Symport or co transport
• Antiport or exchange transport
• SLC transporter mediates uptake and efflux of drugs and metabolite
• OATP ( organic transport poly peptide)
• OCT (cat ion transport)
• present in liver canaliculi and renal tubules
• In met and excretion of drugs and metabolites
• E.g. absorption of glucose in intestine and r tubules SGLT1
and 2
Drug Transporters: Overview
Intestinal efflux:
P-gp, MRP2, BCRP Biliary excretion: Hepatic uptake:
Intestinal uptake: P-gp, BCRP, MRP2, OATP-A, -B, -C, -8, NTCP,
BSEP, MDR3 OAT1, OCT1
ASBT, OCT1, OATP-B,
OATP-A

Intestine Fecal excretion

PO dosing

IV administration
Vascular space Liver
Renal secretion:
OAT1-3, OCT2, MRP2,
MRP4, P-gp
Brain
Kidney
Urinary excretion
Brain transport:
P-gp, BCRP, MRP2
OAT3 (OATP-A, MCT) Interstitial space
Renal reuptake:
OATP-A, PepT2

• Transporters contribute to the absorption, distribution and elimination of

drugs, metabolites, various endogenous molecules, vitamins, and nutrients
• Tissue entry of drugs can be either facilitated or hindered by transporters
Active Transport
pinocytosis
 Effect of pH
• Non-ionic means only the un-ionized or neutral form of the
drug can pass through the membrane. The membrane is primarily
lipid, so charged molecules do not readily pass through it. Thus, the
only form that can be absorbed is the neutral or non-ionized form.
• Pka=PH at which the concentration of ionized to unionized forms are
equal
• If the pKa of the drug is such that the pH of the intestine makes it
ionized, then it will be poorly absorbed.
• If the pKa of the drug is such that some portion of it is in the neutral
form, then it will diffuse through the membrane leaving behind any
ionized form in the intestine.
• There is always an ongoing rapid equilibrium between the dissolved
forms of the drug, between the ionized and nonionized forms.
• Once the non-ionized form of the drug leaves the compartment it is
in (the intestine) then the two forms are no longer in equilibrium.
Immediately some of the ionized form with become non-ionized to
re-establish the equilibrium. Then more non-ionized form is present
and can be absorbed, thus putting the two forms out of equilibrium,
so some more will become non-ionized and so on in a continual
cycle. The trick is that the pKa and pH must be sufficiently close so
that some fraction is non-ionized to start with. Usually 0.1% is
sufficient.
• 3. All that said, pH is not a major determinant of drug absorption.
Because even 0.01-0.1% of the non-ionized form is sufficient to
allow absorption of some drug, thus causing more to become non-
ionized and subsequently be absorbed, the passage of the drug
through the intestine is usually slow enough to allow complete
absorption.
Lipid-Water Partition
Coefficient
– The ratio of the concentration of
the drug in two immiscible
phases: a nonpolar liquid or
organic solvent (representing
the membrane); and an aqueous
buffer, pH 7.4 (representing the
plasma)
 Lipid-Water Partition
Coefficient
• The higher the lipid/water p.c. the greater
the rate of transfer across the membrane
– polarity of a drug, by increasing ionization
will the lipid/ water p.c.
– polarity of a drug, suppression of ionization
will the lipid/ water p.c.
 •PH of drugs
• many drugs are weak acid or base
• For a weak base
• Neutral molecule that can form a cation (Positively charged) by
combining with proton
• E.g.pyrimethamine------- pyrimethamine neutral + proton
ionization is
• BH+ _____________ B + H+
• Dissociation constant pka is given by Henderson Hasselbalch
equation
PH = Pka + log (B) unionized
---------------------------
(BH+) ionized
• For a weak acid
• Neutral molecules can reversibly dissociates into anion ( - ively
charged molecule) and proton
• e.g. Aspirin Neutral)______ aspirin anion + proton
HA---- A + H+
• ionized

------------
unionized
• pH = Pka + log A-
• ----------
• (HA)
• Ionized species BH or A has very low lipid solubility and virtually
unable to permeate membrane
 Except where specific carrier is required
• Lower the ph relative to pka greater the fraction of drug
in protonated form
• Uncharged form is more lipid soluble
• More of a weak acid will be lipid soluble at acidic ph
• While more of basic drug will be in lipid soluble form at
alkaline ph, B or AH will depend on the chemical nature
of drug
• For many drugs the uncharged species is sufficiently lipid soluble to
permit rapid permeation except amino glycosides due to oH group
makes it hydro philic
• The ratio between the two forms is determined by PH at the site of absorption and
by the strength of the weak acid or base presented by pka
• protonated
• Log ---------------- = Pka - pH
• unprotonated
• Lower the ph relative to pka, stronger the acid, greater the fraction in protonated
form
• If the con. Of ionized drug = unionized drug = 1
• Log 1 is 0 under this
• pH = pka
• 50% ionized= 50% unionized
• If ph is increased by 1
• A
• ---------- =10 times increase in ionization
• HA
• If pH is reduced by 1
• A- 1

• ____= ------
• HA 10
 Ion Trapping cont:
Body fluids where a pH difference from
blood pH will favor trapping or
reabsorption: stomach contents
small intestine
breast milk
aqueous humor (eye)
vaginal secretions
prostatic secretions
 Ion Trapping:
Kidney:
Nearly all drugs filtered at the glomerulus:
Most drugs in a lipid-soluble form will be absorbed
by passive diffusion.
To increase excretion: change the urinary pH to favor
the charged form of the drug:
• Weak acids: excreted faster in alkaline pH (anion
form favored)
• Weak bases: excreted faster in acidic pH (cation
form favored)
• A 3year old child is brought to the emergency deptt ingested
overdose of promethazine( weak base) with pka 9.1
• Urinary excretion accelerated by administration of NH4Cl an
acidifying agent
• U.excretion accelerated by giving NaHCO3 AN ALKANIZING
AGENT
• MORE OF DRUG IONIZED AT BLOOD ph THAN STOMACH PH
• Absorption of drug faster from stomach than from s.intestine.
• Aspirin is a weak acid with pka 3.5
• What percentage of a given dose will be in
lipid soluble form at a stomach ph of 2.5
• About 10%
• About 1%
• About 90 %
• about 99%
 Absorption
• Movement of drug from site of its administration into circulation
• Fraction of administered drug
• Rate of absorption
• Factors affecting absorption
• 1 aqueous solubilty
• 2 concentration

• Must dissolve in aqueous media before absorbed

• For poorly soluble (aspirin, griseofulvin)
• Rate of dissolution governs rate of absorption
• Watery solu absorbed faster than solid or oily solu
• 2 concentration
• Diffusion depends on conc gradient
• con solu absorbed faster than diluted
• 3 Area of absorbing surface
• Larger area in absorption
• e,.g.small intestine due to villi

• Morphine, quinine
• 4 Vascularity of the surface
• 5 routes of administration
• Oral
• Absorption in stomach is slow due to thick mucosa
• Acidic drugs are absrbed in unionized form in acidic
medium e.g. aspirin, barbiturates
• Larger surface area e.g. lungs and intestine
• 6 Presence of food
• Dlutes the drug and retard absorption
Food delays gastric emptying most drugs are absorbed when taken on
empty stomach
• 7 Presence of other agents
• Poorly absorbed complexes e.g tetracycline with milk
• Vit C increase iron absorption
• 8 degree of ionization
• Highly ionized drugs e.g.gentamicin, neostigmine poorly absorbed
orally
• Penicillic G by acid
• Insulin by peptidases
• Enteric coated and sustained release prepration used to overcome acid
lability, gastric irritancy and brief duration of action.
• 9 Diseases
• Diarrhea
• Malabsorption
• 10 Drugs
• Metoclopromide
• Anticholinergics
• 11 Particle size
• Smaller the particle size better absorption
• E.g. corticosteriods
• Formulation
• Lactose, sucrose, starch, phosphate used as excipient in tablets
• 12 Chemical nature of molecule
• Inorganic iron prep are better absorbed
from GIT than organic
• 13 Blood flow
• In shock, vasoconstrictor
• BF is dec to intestine
Luminal effect
• Absorbtion is affected by other concurrently ingested
drugs
• E.g. formation of insoluble complexes
• Tetracyclines with iron prepration and antacids
• Can be minimized by 2-3 hour interval
• Gut wall effect
• Altering motility (anticholinergic , antidepressant)
• Causing mucosal damage (neomycin, methotrexate)
• S/c or I/m
• Absorbtion is slower s.c than I.m.
• Application of heat and muscular exercise
increase absorp by blood flow
• Adrenaline retard
• Topical site
• Depend on lipid solubility
• Can cause systemic toxicity e.g.hydrocotisone
 Bioavailability
Measure of fraction of administered dose of a drug that
reaches systemic circulation in unchanged form

F=f х (1-ER)
E.g. morphine
 f=extent of absorp
 ER = extraction ratio
 E.g. morphine
 f = 1 completely absorbed so that loss is negligible
 ER = 0.67
Bioavailability = 33%
Representative plasma concentration–time relationship
after a single oral dose of a hypothetical drug.

•
• AUC oral
• Bioavailability=-------------------×100
• AUC injected
 Factors affecting bioavailability
 Factors influencing bioavailability

 The absolute bioavailability of a drug, when administered by an

extravascular route, is usually less than one (i.e. F<1). Various
physiological factors reduce the availability of drugs prior to their entry into
the systemic circulation,
 Such factors may include:
 Extent of absorption
Solubility of drug
 Physical properties of the drug (hydrophobicity, pKa, solubility)
if too hydrophilic cannot cross lipid membranes e.g. atenolol
 Too lipophilic not soluble to cross water layer e.g. acyclovire
 The drug formulation (immediate release, excipients used, manufacturing
methods, modified release - delayed release, extended release, sustained
release, etc.)
`
 If the drug is administered in a fed or fasted state
 Gastric emptying rate
 Circadian differences dawn effect and effects e.g. insulin

 Interactions with other drugs (e.g. antacids, alcohol, nicotine)

 Interactions with other foods (e.g. grapefruit juice, cranberry
juice)
 Transporters: (e.g. P-glycoprotein)
 Health of the GI tract
Enzyme induction/inhibition by other drugs/foods:
 Enzyme induction (increase rate of metabolism). e.g. Phenytoin
(antiepileptic) induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4
• Enzyme inhibition (decrease rate of
metabolism). e.g. grapefruit juice inhibits CYP3A --> higher
nifedipine concentrations
. Whether a drug is taken with or without food will affect absorption,
• other drugs taken concurrently may alter absorption and first-pass
metabolism,
• intestinal motility alters the dissolution of the drug and may affect
the degree of chemical degradation of the drug by intestinal
microflora.
• Disease states affecting liver metabolism or gastrointestinal
function will also have an effect
 First pass elimination
 After absorption drug enters to liver via portal blood prior to systemic circulation
 A drug can be metabolized in gut wall or in portal blood but most commonly in liver. These
sites responsible for reduction in bioavailability and this process is known as first pass
elimination
 Effect of 1st pass hepatic elimination on bioavailability depends extraction ratio
 ER= CL liver/Q
 Chemical instability
 Penicillin G
 insulin
 Iv = 100%
 Im/ sc =75 – 100
 Oral =30
 Rectal = 30< 100
 Inhalation = 5 to < 100
 Transdermal 80 to<100

3_graphs_0_order.jpg
• Individual Variation in Metabolic Differences

• Age: In general, drugs metabolized more slowly in fetal, neonatal, and geriatric
populations

• Phenotypic differences, enterohepatic circulation, diet, gender.

• Disease state

• e.g. hepatic insufficiency, poor renal function

• Each of these factors may vary from patient to patient (inter-individual variation), and
indeed in the same patient over time (intra-individual
• Two related drugs are bioequivalent if they show comparable
bioavailability and similar time to acheive peak blood conc
• Bioinequivalence
• Two related drugs with a significant difference in bioavailability
• Therapeutic equivalence
• Two similar drugs are therapeutically equivalent if they have
comparable efficacy and safety
• Clinical effectiveness depends on
• Max drug conc.
• Time after administration required to reach peak conc
• So two drugs are bioequivalent may not be therapeutically
equivalent
 Bioavailability

• F=f х (1-ER)

• f=extent of absorp
• ER = extraction ratio
• E.g. morphine
• F = 1 completely absorbed so that loss is negligible
• ER = 0.67
• Bioavailability = 33%
• Representative plasma concentration–time relationship after a
single oral dose of a hypothetical drug.
• Measure of fraction of administered dose of a drug that reaches
systemic circulation in unchanged form
•