RIFT VALLEY UNIVERSITY ABICHU CAMPUS
PHARMACY DEPARTMENT
BIOPHARMACEUTIC & CLINICAL
PHARMACOKINETICS
Tesfaye Gabriel (PhD in Pharmaceutics)
Outline
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Introduction
GI physiology and membrane physiology
Factors influencing drug absorption
Mechanisms of Transport
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Biopharmaceutics Introduction…
• study of the factors
influencing the
bioavailability of a drug
in man and animals
and the use of this
information to
optimize
pharmacological or
therapeutic activity of
drug products in
clinical application.
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Biopharmaceutics
• study of the influence of formulation on
therapeutic activity of a drug product.
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Biopharmaceutics
• studies how
– Route of administration
– Dosage form
– Physicochemical cxs of the
API
Affect rate & extent
of absorption
pk
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PK and PD
PK
is the study of what the body does to a drug
PD
is the study of what a drug does to the body
Rationale
• The development of biopharmaceutic
principles allowed for the rational design of
drug products, which would enhance the
delivery of active drug, and optimize the
therapeutic efficacy of the drug in the patient.
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Drug Product
• a finished dosage form that contains an active
drug ingredient generally, but not necessarily,
in association with inactive ingredient.
• formulation or matrix in which the drug is
contained
• The term may also include a dosage form that
does not contain an active ingredient intended
to be used as placebo.
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Drug Action
• result of an interaction between the drug
substance and functionally important cell
receptors or enzyme systems.
• This response is due to the alteration in the
biologic processes that were present prior to
the drug administration.
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• In vitro – glass
➢ referring to a process or reaction carried out in
a culture dish or test tube
• In vivo – in the living organism
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Effects of Biopharmaceutics
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Generic equivalency
Drug availability
Therapeutic efficacy
Drug substitution
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Primary concern of biopharmaceutics is bioavailability
In other words:
•The nature of the drug
•The route of delivery and
•The formulation of the DF
can determine whether an
administered drug is:
➢therapeutically effective
➢Toxic or
➢Has no effect at all
Optimum amount of active drug is needed in systemic circulation
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what is pk?
• The word is derived from two Greek words
– Pharmakon => drug
– Kinesis → motion or change of rate
• The study and characterization of the time course of drug
absorption and disposition
– Disposition =distribution and elimination
– Elimination =metabolism and excretion
• The study of rate processes involved in the absorption,
distribution, excretion and metabolism (ADME)
• The relationship of ADME to the pharmacological, therapeutic
or toxic response
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Schematic presentation of drug absorption, distribution and elimination
distribution
In blood
elimination
Start here
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Effects of Biopharmaceutics
• Drug product selection
*drug product should be
cost-effective
*drug product selection
should be according to the
patient’s capability
*drug product selection
should be based upon the
patient’s diagnosis
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Aim
• The aim of biopharmaceutics is to adjust the
delivery of drug to the general circulation in
such a manner as to provide optimal
therapeutic activity for the patient.
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Aim
• Biopharmaceutic studies allow drugs to be
formulated rationally based on
pharmaceutic properties.
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Some Pharmaceutic Properties
• Some drugs are intended for topical or local
therapeutic action at the site of administration.
• For these drugs, systemic absorption is
undesirable.
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Some Pharmaceutic Properties
• Drugs intended for local activity generally
have a direct pharmacodynamic action
without affecting other body organs.
• These drugs may be applied topically to the
skin, nose, eyes, mucous membranes, buccal
cavity, throat and rectum.
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Factors Affecting Biopharmaceutics
• a. physical state of the drug
- according to the 4 states of matter
❖The crystal or amorphous forms and/or the
particle size of a powdered drug have been
shown to affect the dissolution rate, and thus
the rate of absorption, for a number of drugs.
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Factors Affecting Biopharmaceutics
❖By selective control of
the physical
parameters of a drug,
biologic response may
be optimized.
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b. dosage form
- delivery system that the drug could be
available or administered.
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b. dosage form
❖ Each of dosage unit is designed to contain a specified quantity
of medication for ease and accuracy of dosage administered.
❖ Each product is a formulation unique unto itself
❖ Biopharmaceutic considerations often determine the ultimate
dose and dosage form of a drug product.
❖ For example, the dosage for a drug intended for local activity,
such as a topical dosage form, is often expressed in
concentration or as % of the active drug in the formulation.
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Biopharmaceutics
• Biopharmaceutic
studies must be
performed to ensure
that the dosage form
does not irritate, cause
an allergic response or
allow systemic drug
absorption.
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c. route of administration
• each route of drug application presents
special biopharmaceutic considerations in
drug product design.
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c. route of administration
• by carefully choosing the route of drug
administration and properly designing the drug
product, the bioavailability of the active drug can
vary from rapid and complete absorption to a slow,
sustained rate of absorption or even virtually no
absorption, depending on the therapeutic objective.
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Example
• The design of a vaginal
tablet formulation for
the treatment of a
fungus infection must
consider ingredients
compatible with
vaginal anatomy and
physiology.
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Example
• An eye medication may require special
biopharmaceutic considerations including
appropriate pH, isotonicity, local irritation to
the cornea, draining by tears, and concern for
systemic drug absorption.
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Scope of Biopharmaceutics
1. Encompasses all possible effects observed
following the administration of the drug
in the various dosage forms.
2. Encompasses all possible effects of various
dosage forms on biological response
3. Encompasses all possible physiological
factors which may affect the drug in
various dosage forms.
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A primary concern in
biopharmaceutics
Bioavailability
refers to the measurement of the rate and extent of
active drug that reaches the systemic circulation.
means access to the bloodstream
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Drug Bioavailability Process
Drug in the drug product
Solid drug particles
Drug in solution
Drug in the body
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GI Physiology and Membrane Physiology
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• Very little drug absorption occurs
→ small SA
• High biopharmaceutical importance:
→ Gastric emptying can dictate drug absorption
from SI.
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Small intestine
• Longest (4 - 5 m) and most convoluted part
→ Extend from pyloric sphincter to ileocaecal junction
2 Main functions:
- Digestion
- Absorption
3 parts:
• – Duodenum: 20 - 30 cm
• – Jejunum: ~ 2 m
• – Ileum ~ 3 m
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•
•
•
•
SI wall has rich network of blood and lymphatic vessels
→ ~ 1/3 cardiac output flows through GI viscera
SI receives blood from superior mesenteric artery
Blood leaves SI via hepatic portal vein to liver and then to
systemic circulation
• Drugs susceptible to metabolism by liver are degraded
→ hepatic presystemic clearance, first-pass metabolism
• SI has enormous SA ~ 200 m2 in adult
→ Several adaptations!
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• Microvilli: brush-like structures covering villi
- ~ 1 μm long & 0.1 μm wide
→ ~ 600 – 1000 per villus
→ largest increase in SA
Significant biopharmaceutical importance:
• → Most nutrients and drugs absorbed from SI
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Three mechanisms for increasing surface area of the small intestine. The increase in
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surface area is due to folds of Kerkring, villi, and microvilli.
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Nature of cell membrane
• For systemic drug absorption, the drug must cross cellular
membranes
• After oral administration, drug molecules must cross the
intestinal epithelium by going either through or between the
epithelial cells to reach the systemic circulation
• Once in the plasma, the drug may have to cross biological
membranes to reach the site of action.
• Therefore, biological membranes potentially pose a significant
barrier to drug delivery.
• permeability of drug molecules depends on
– molecular structure of the drug and
– physical and biochemical properties of the cell
membranes.
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Nature of cell membrane
Membranes are major structures in cells
• 70 to 100 Å in thickness
• composed primarily of phospholipids in the form of a bilayer
interdispersed with carbohydrates and protein groups
• surrounding the entire cell (plasma membrane)
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• acting as a boundary between the cell and the interstitial fluid
• enclose most of the cell organelles.
• Functionally, cell membranes are semipermeable partitions
that act as selective barriers to the passage of molecules.
• Water, some selected small molecules, and lipid-soluble
molecules pass through such membranes,
• whereas highly charged molecules and large molecules, such
as proteins and protein-bound drugs, do not.
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Steps involved prior to a pharmacological effect after administration of a rapidly
disintegrating tablet.
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Transit of Pharmaceuticals In GIT
• Most DFs transit esophagus in
----------- <15 s
→Tablets/capsules taken in supine position are liable to
lodge in esophagus esp. when taken without water
→Chance of adhesion depend on shape, size and type of
formulation
→ Delay in reaching stomach may delay drug's onset of
action
→ Cause damage or irritation to esophageal wall, e.g.
KCl tablets
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Gastric emptying
• Gastric emptying time is time DFs take to traverse
stomach.
→ Gastric emptying rate, Gastric residence time
• GET is highly variable
→ Normal GET range b/n
5 min and 2 hrs
→ GET over 12 hrs for large single units
• GET depends on DF type, Fed/fasted state of
stomach
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Two patterns of activity are observed when food is
ingested:
• 1. Proximal stomach relaxes to receive food, gradual
contractions move contents distally
• 2. Distal stomach contracts to mix and break food
particles and move them towards pyloric sphincter
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• Pyloric sphincter allows liquids and small food
particles.
• Others are retropulsed into antrum for size
reduction.
• In fed state, liquids, pellets and disintegrated tablets
empty with food
→ Large unit DFs (SR or CR) can be retained for long.
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• In fasted state, stomach is less discriminatory b/n DFs
– Characterized by cyclic fluctuations of contractions
k.a. interdigestive migrating myoelectric complex
(IMMC)
→ Initiate in antrum and migrates distally to small
intestine
→ Governs gastric emptying
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IMMC is characterized by 4 phases
• Phase I - relatively inactive (quiescent) period of 45 60 min with only rare contractions
• Phase II - intermittent and irregular contractions of ~
30 min
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• Phase III - powerful evenly spaced peristaltic
contractions, open pylorus and clear stomach of
residual material ---Housekeeper Wave
⇒ 5 to 15 min
⇒ Play important role in emptying indigestible solids
- bone, fiber and foreign bodies
⇒ Critical for large unit DFs!
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• Phase IV - short transition period b/n Phase III
and Phase I.
• Cycle recurs every 1.5 to 2 hrs until meal is
ingested.
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Motor activity responsible for gastric emptying of indigestible solids.
Migrating myoelectric complex (MMC), usually initiated at proximal stomach
or lower esophageal sphincter, and contractions during phase 3 sweep
indigestible solids through open pylorus.
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Many factors influence gastric emptying:
• DF (liquid vs. solid, unit DFs vs. multiparticulate DFs)
• presence and composition of food
• postural position
• drugs
• disease state
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• Factors delaying GET
→ Fats and fatty acids in diet
→ High viscosity of diet
→ Lying on left side
→ Diseases: Mental disturbance/depression,
hypothyrodism, gastric ulcer
→ Drugs: propantheline, atropine (antimuscarinic)
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• Factors promoting GET
→ Fasting
→ Lying on right side
→ Diseases: anxiety, hyperthyrodism
→ Drugs: Metoclopramide (antiemetic and
gastroprokinetic)
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Small Intestinal Transit
• Small intestinal transit time is relatively constant,
~ 3 hrs
• SI does not discriminate b/n solids and liquids, b/n
DFs, or b/n fed and fasted states
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• Two movements (propulsive and mixing)
⇒ Propulsive movement determine SITT
• SITT is particularly important for
→ CR, SR, PR DFs (release drug slowly);
→ Enteric-coated DFs (release drug in SI);
→ Drugs that dissolve slowly in intestinal fluids; and
→ Drugs absorbed by intestinal carrier-mediated
transporters
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Colonic Transit
• Long and variable
• Characterized by short bursts of activity followed by
long period of stasis
→ CT vary from 2 - 48 hrs
• Mouth-to-anus transit time is longer than 24 hrs
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Barriers to absorption
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Environment inside GI Lumen
GI pH
• Luminal pH varies considerably along GIT
• Gastric fluid is highly acidic (pH ~ 1 - 3.5) in fasted
state
• Following ingestion of meal, buffered to less acidic
pH
→ Typically, 3 - 7 following meal
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• Returns to fasted-state value in 2 - 3 hrs depending
on meal size
Important consideration for
- chemical stability,
- drug dissolution or absorption
• Intestinal pH is higher
→ Neutralization with HCO3
- secreted by pancreas
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• GI pH influence absorption of drugs in variety of
ways: pH-dependent hydrolysis
Eg. Penicillin G (benzylpenicillin)
→ Degradation depends on gastric residence time
and pH ⇒ Gastric instability preclude oral use
• Erythromycin and omeprazole degrade rapidly at
acidic pH
→ Formulated as enteric-coated DFs
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Luminal enzymes
• Pepsin is primary enzyme in gastric juice.
• Lipases, amylases and proteases are secreted from
pancreas in SI in response to ingestion of food
• Colonic bacteria secrete enzymes capable of range of
reactions
→ Drugs and DFs to target colon
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• → Pepsins and proteases degrade protein and
peptide drugs
• →Drugs resembling nutrients, such as nucleotides
and fatty acids, may be susceptible to enzymatic
degradation
• → Lipases may affect release from fat/oil-containing
DFs
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• Sulphasalazine (IBD) - Prodrug
- 5-aminosalicylic acid linked to sulphapyridine via azo
bond
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• Latter makes it too large and hydrophilic to be
absorbed
→ Transported intact to colon
→ Bacterial enzymes reduce azo bond to release 5-ASA
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Influence of food
• Food influence rate and extent of absorption (direct
or indirect)
--Complexation of drugs with components in diet
• Becomes issue when irreversible or insoluble complex
is formed
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• TTC forms non-absorbable complexes with Ca2+ and
Fe2+
• Not taken with Ca2+and Fe2+ containing products
→ milk, iron preparations or indigestion remedies
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Alteration of pH
• Food increase stomach pH
→Decrease rate of dissolution and absorption of
weakly basic drug and increase that of weakly acidic
one
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Alteration of gastric emptying
• Fatty foods reduce gastric emptying and delay onset
of action
Stimulation of GI secretions
• Pepsins produced in response to food may degrade
drugs
• Fats stimulate secretion of bile
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• Bile salts are surface-active agents
→Increase dissolution of poorly soluble drugs and
enhance their absorption
→Bile salts form insoluble and non-absorbable
complexes with some drugs, such as neomycin,
kanamycin and nystatin.
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• Competition b/n food and drugs for specialized
absorption mechanisms.
Competitive inhibition of absorption of drugs with
chemical structure similar to nutrients.
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Increased viscosity of GI contents
• Food provides viscous environment.
→ reduce rate of drug dissolution and
→ diffusion from lumen to absorbing membrane lining
GIT
• Decrease bioavailability!
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Food-induced changes in presystemic metabolism
• Grapefruit juice inhibits intestinal cytochrome P450
(CYP3A family)
→ ↑ bioavailability of susceptible drugs
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Clinically relevant interactions
• Terfenadine (antihistamine), now replaced by
fexofenadine
• Cyclosporin (immunosuppressant)
• Saquinavir (protease inhibitor)
• Verapamil (calcium channel blocker)
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Food-induced changes in blood flow
• Blood flow to GIT and liver increases after meal
→ Increase rate at which drug is presented to liver
→ Larger fraction of drug escapes first-pass metabolism
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Enzymes saturate by increased rate of presentation
- Propranolol (beta-blocker)
- hydralazine (vasodilator)
- dextropropoxyphene (opioid analgesic)
• ⇒ Food increases bioavailability of drugs susceptible
to first-pass metabolism
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The unstirred water layer
• Aqueous boundary layer is stagnant layer of water,
mucus and glycocalyx (glycoprotein) adjacent to
intestinal wall.
– Incomplete mixing of luminal contents near mucosa.
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Barriers to absorption
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• ~ 30 - 100 μm thick
• Provide diffusion barrier to drugs
• Some drugs complex with mucus reducing availability
for absorption
------4o ammonium compounds
------erratic and incomplete absorption
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Mechanisms of Transport
Mechanisms of drug transport:
→ Transcellular (across cells)
– Simple passive diffusion
– Carrier-mediated transport
o Active transport
o Facilitated diffusion
– Endocytosis
– Miscellaneous: Ion-pair Formation, convective/pore
transport
→ Paracellular (between cells)
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Passive diffusion:
Preferred for relatively small lipophilic molecules many drugs
→ Molecules travel from region of high conc. to low
conc.
→ Low conc. is maintained by blood flow (Sink
Condition)
⇒ From lumen to blood
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Described mathematically by Fick's first law
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→ Rate of diffusion (dC/dt) ∝ conc. gradient across
membrane
k incorporates diffusion coefficient in GI membrane (D),
thickness (h) and SA of membrane (A)
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Rate of passive diffusion depends on
- Physicochemical properties (molecular size,
partition coefficients, ...)
- Nature of membrane (SA and thickness of
membrane)
- Conc. gradient of drug across GI membrane
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• Blood acts as 'Sink' for absorbed drug (Cg » Cb)
• Because for given membrane, D, A and h are
constants:
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• A first-order kinetic process
→ Rate ∝ conc. in GI fluids
→ Valid for most drugs
• Absorption rate of hydrocortisone from human SI ∝
drug conc. over 2000-fold conc. range (0.05 – 100
mg/L)
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Assumption: Drug exists solely in single absorbable
species
• Many drugs are weak electrolytes
→ Exist as unionized and ionized species (pKa , pH )
→ GI membrane is more permeable to unionized form
(greater lipid solubility)
⇒ Rate is related to fraction of unionized form
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Carrier-mediated transport
• Most drugs are absorbed from GIT via passive
diffusion
• Few lipid insoluble drugs and many nutrients are
absorbed by carrier-mediated transport
→ Carrier binds drug and transports it across
membrane
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• Explained by shuttling process across
epithelial membrane
→ Drug forms complex with carrier
→ Drug-carrier complex moves across
membrane
→ Drug liberated on other side
∗ Free carrier returns to initial position in cell
membrane adjacent to GI lumen.
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Active transport
• Takes place when intestine transport uphill against
conc. gradient
→ Energy consuming process
• Large number of active transport systems in SI
→ Peptide T, nucleoside T, sugar T, bile acid T,
amino acid T, organic anion T and vitamin T
→ Each carrier system is conc. in specific
segment of GIT and has its own substrate specificity
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➢Bile acid transporters only found in ileum
→ Developed for nutrients and chemicals essential to
life
• Electrolytes: Na+, K+, Ca2+, Fe2+, Cl-, HCO3• Nutrients: amino acids, sugars
• Vitamins: thiamine, riboflavin, nicotinic acid,
pyrdoxine and cynocobalamin
• Bile salts
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➢ Drug structurally resembling natural substance that is
actively transported is likely to be transported by
same carrier
• Penicillins, cephalosporins, ACE inhibitors and renin
inhibitors rely on peptide transporters for efficient
absorption
• Nucleosides and their analogues for antiviral and
anticancer drugs depend on nucleoside transporters
• 5-fluorouracil is transported by pyrimidine
transport system
• L-dopa and α-methyldopa are transported by
amino acid transporters
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• Rate of absorption ∝ conc. of absorbable species only at low
conc.
→ Becomes saturated at higher concs.
→ Capacity limited process
→ Further increase in conc. will not increase rate
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Rate of Absorption in Carrier-Mediated Transport
• Number of apparent carriers in intestinal membrane is
limited
• Rate is described Michaelis-Menten equation
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• At low drug conc., Km >>Cg
→ First order process
• At large drug conc., Cg >>Km
→ Constant rate, Vmax
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• BA of drugs absorbed by carrier mediated transport
decrease with increasing dose.
→ Riboflavin, thiamine, ascorbic acid
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• Competitive inhibition of absorption is characteristics
of carrier-mediated transport
• Inhibition of absorption observed with agents that
interfere with cell metabolism
– sodium fluoride, cyanide or dinitrophenol
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• Some substances may be absorbed by simultaneous
carrier-mediated and passive transport processes
→ Pyrimidines - uracil and thymine
• Active transport plays important role in renal and
biliary excretion of many drugs and metabolites
Characteristics of active carrier-mediated
– Transportation against conc. gradient
– Selectivity to substrate
– Specific location in GIT
– Saturability
– Competitive inhibition by substrate analogues
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Facilitated diffusion
• Cannot transport substance against conc. gradient
→ Does not require energy input
→ Require conc. gradient as driving force
• Solutes are transported downhill but at much faster
rate than would be anticipated based on molecular
size and polarity
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Like active transport, it is
• saturable,
• substrate selective,
• subject to inhibition by competitive inhibitors and
• specific in GI location
• Plays very minor role in drug absorption
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Convective transport or pore transport
• Very small molecules such as water, urea and low
molecular weight sugars and organic electrolytes are
able to cross cell membranes rapidly as if there is no
barrier for their passage.
• Explained by aqueous filled pores or channels
assumed to be present in cell membrane.
• Radius of channel is estimated to be in order of 0.4
nm.
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• Due to molecular size limitations, minor
importance w.r.t. GI absorption of large water
soluble drug molecules or ions
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Ion-pair formation
• 4o NH4 compounds and TTCs are ionized over entire GI
pH
→ Cannot partition directly into lipoidal membrane
→ Too large to pass through aqueous filled pores in
membrane.
• Interaction with oppositely charged endogenous organic
ions form ion-pair whose overall charge is neutral.
• Ion-pair diffuses more easily across lipoidal cell
membrane
→ ↑ lipid solubility
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Vesicular transport
• Plasma membrane of cell invaginates and invaginations
become pinched off, forming small intracellular
membrane-bound vesicles enclosing volume of material
→ Energy dependent uptake
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• After invagination, material is transferred to lysosomes
and digested
• Some material escape digestion and migrate to
basolateral surface of cell and exocytosed
• Endocytosis is primary mechanism of transport of
macromolecules
→ Sabin Polio vaccine and various large proteins
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Paracellular pathway
• Transport of materials in aqueous pores b/n cells
• Cells are joined together via tight junctions
→ Intercellular spaces occupy ~ 0.01% of total SA of
epithelium
• Tightness of junctions vary b/n different epithelia
→ Absorptive epithelia, such as SI tend to be leakier
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• Paracellular absorption is important for transport of
→ Ions such as Calcium
→ sugars, amino acids and peptides at conc.
above carrier capacity
• Small hydrophilic and charged drugs cross GI
epithelium via paracellular pathway
• Molecular weight cut-off ~ 200 Da
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Efflux of drugs from intestine
• Counter-transport efflux proteins expel specific drugs
back into lumen of GI tract
• Key counter transport protein is P-glycoprotein
• Expressed at high levels on apical surface of jejunum
• Also present on surface of many other epithelia and
endothelia in body, and on surface of tumor cells
→ Cause MDR in tumor cells
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• Drugs with wide structural diversity are susceptible to
efflux from intestine via P-glycoprotein.
→ Detrimental on drug bioavailability
- Cyclosporine (immunosuppressant)
- Nifedipine and Verapamil (Calcium Channel Blocker)
- Paclitaxel (Anticancer)
- Digoxin (Cardiac glycoside)
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Pump drugs out of cells in similar way as nutrients and
drugs are actively absorbed across GI membrane
* Requires energy:
– work against concentration gradient
– competitively inhibited by structural analogues
– inhibited by inhibitors of cell metabolism
– saturable process
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Presystemic metabolism
• Gut-wall metabolism
- Cytochrome P450 enzyme, CYP3A, present in
intestinal mucosa
→ Cyclosporin, Saquinavir
• Hepatic metabolism
- Liver is primary site of drug metabolism and acts as
final barrier for oral absorption
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∗ Bioavailability of susceptible drug may be reduced to
such extent as to render GI route of administration
ineffective, or to necessitate oral dose which is many
times larger than i.v. dose,
→ Propranolol: ~ 30 % of oral dose is available to
systemic circulation owing to first-pass effect
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• Bioavailability of SR propranolol is even less
→ drug is presented more slowly, and liver is
capable of extracting and metabolizing larger portion
• Other drugs susceptible to large first-pass effect
- lidocaine (anaesthetic)
- imipramine (tricyclic antidepressant)
- pentazocine (analagesic).
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PHYSICOCHEMICAL FACTORS INFLUENCING
DRUG ABSORPTION
Dissolution and Solubility
• Precondition for absorption of solid drugs
Dissolution: rate of solution of solid in solvent
Solubility: extent to which dissolution proceeds under
given set of conditions
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• Dissolution of solid in liquid is composed of
two stages
❖ Interfacial reaction liberates solute molecules
from solid phase
➢ Involves phase change (molecules of solid become
molecules of solute in solvent)
➢ Solution in contact with solid will be saturated
(conc. will be Cs, saturated solution)
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❖ Solute molecules migrate through boundary layers
(static layer of liquid surrounding wetted solid surfaces)
to bulk of solution
➢Once solute passes boundary layer, rapid mixing
occurs and conc. gradient is destroyed; conc. will be C.
• Conc. of solution in boundary layer changes from being
Cs at crystal surface to bulk conc. C at its outermost limit.
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• Rate of diffusion of dissolved solute across
boundary layer determines rate of dissolution
➢ Obey Fick's law of diffusion
➢ Rate ∝ conc. difference b/n two sides of diffusion layer
dC/ dt = kΔC
Where:
• k is dissolution rate constant (s-1)
• ΔC is difference in conc. at solid surface (Cs) and bulk (C)
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Diagram of boundary layers and concentration change
surrounding a dissolving
particle
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• Noyes-Whitney equation (1897):
Where:
▪ D - diffusion coefficient of drug
▪ A - effective SA of drug particle
▪ h - thickness of diffusion layer
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Assumptions:
•
•
•
•
Drug particles are spherical and equal in size
Dissolution process is controlled by diffusion
No chemical reaction b/n drug and components of fluid
Thickness of diffusion layer (h) and saturation solubility (Cs)
are constant irrespective of particle size
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Surface area and particle size
➢ Particle size reduction result in increased bioavailability
→ Dissolution-rate limited absorption
Griseofulvin anti fungus
→Reduction of particle size from ~ 10 μm (specific SA = 0.4 m2 g1) to 2.7 μm (specific SA = 1.5 m2 g-1) produced approx.
doubled amount of drug absorbed in humans
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• Many poorly soluble, slowly dissolving drugs are
presented in micronized form to increase SA
✓ Digoxin (Cardiac glycoside)
✓
✓
✓
✓
✓
✓
✓
Nitrofurantoin (Antifungal)
Medroxyprogesterone acetate (Hormone)
Danazol (Steroid)
Tolbutamide (Antidiabetic)
Sulphadiazine (Antibacterial)
Naproxen and Ibuprofen (NSAID)
Phenacetin (Analgesic)
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• Improvement in bioavailability can result in increased
side effects
➢ Important to control particle size
➢ Some Pharmacopoeia state requirements of
particle size
• For hydrophobic drugs, micronization and other dry
particle size reduction techniques can result in
aggregation
➢ Reduce effective SA exposed to GI fluids
➢ Reduce dissolution rate and bioavailability
Eg., Aspirin, Phenacetin and Phenobarbitone
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Solutions:
➢ Micronize or mill drug with wetting agent or
hydrophilic carrier
➢ Wet milling in presence of stabilizers to achieve
nano-sized particles
• Relative bioavailability of danazol increased 400 %
by administering particles in nano- rather than
micrometer size range.
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• Effective SA of hydrophobic drugs can be increased
by addition of wetting agent to formulation
❖ Tween-80 in fine suspension of phenacetin (< 75 μm)
improved bioavailability vs. same-size suspension without
wetting agent
o Increase wetting and solvent penetration of
particles
o Minimize aggregation of suspended particles
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➢ Wetting effects are highly drug specific!
➢ If increasing effective SA does not increase
absorption rate, it is likely that dissolution process is
not rate limiting
➢ For drugs which are unstable in gastric fluid, particle
size reduction increase chemical degradation
✓ Penicillin G and erythromycin
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Solubility, Cs
➢ Aqueous solubility depends on
• Interactions b/n molecules within crystal lattice
• Intermolecular interactions with solvent
➢ Entropy changes associated with fusion and dissolution.
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➢ In weak electrolytes, aqueous solubilities
depend on pH
❖ Dissolution rate depend on solubility and pH in
diffusion layer
❖ Difference in dissolution rate is expected in
different regions of GI tract
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❖ Solubility of weakly acidic drugs increases with pH
➢ Solubility increase as drug move down GI tract from
stomach to SI
❖ Solubility of weak bases decrease with increasing pH
➢Solubility decrease as drug move down GI tract from
stomach to SI
❖ Important for poorly soluble weak bases to dissolve
rapidly in stomach as rate of dissolution in SI is much
slower
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▪ Weak base ketoconazole (antifungal) is sensitive to
Tagamet
gastric pH
➢ Dosing ketoconazole 2 hrs after cimetidine (reduces gastric
acid secretion) results in significantly reduced rate and extent
Pepcid
of absorption.
▪ Pretreatment with H2 blocker famotidine reduces
peak plasma conc. of dipyrimidole (antiplatelet) by
factor of up to 10.
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Salts
• Alter pH of diffusion layer
• Dissolution rate of weakly acidic drug in
gastric fluid (pH 1 - 3.5) is relatively low
➢If pH in diffusion layer could be increased,
solubility (Cs) in this layer, and hence its
dissolution rate in gastric fluids, is increased even
though bulk pH remain low
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➢ pH of diffusion layer would be increased if basic salt
is formed
E.g., Na+ or K + salts of free acid
➢ pH of diffusion layer surrounding each particle is
higher (e.g. 5 - 6) than bulk (1 - 3.5) because of
neutralizing action of Na+ or K + ions present in
diffusion layer.
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• Salt has higher solubility at elevated pH in diffusion layer
➢Dissolution will be faster
• When dissolved drug diffuses out of diffusion layer into
bulk of gastric fluid, where pH is lower, precipitation of
free acid form is likely to occur.
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❖ Precipitated free acid will be in form of very fine, wetted
particles which exhibit very large total effective SA in
contact with gastric fluids
Large SA facilitate rapid redissolution precipitated
particles
Ensures that conc. of free acid in solution is at or near
Cs
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Dissolution rate of tolbutamide sodium (oral
hypoglycemic) in 0.1 M HC1 is 5000 times faster than
the free acid
• Oral administration of
- Tolbutamide sodium → very rapid decrease in blood sugar,
followed by rapid recovery
- Tolbutamide → slower decrease of blood sugar that was
maintained over longer period of time
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• Barbiturates are often administered as sodium salts
to achieve rapid onset of sedation and provide more
predictable effects.
• Naproxen sodium is absorbed faster and is more
effective than naproxen in treating mild to moderate
pain.
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❖ Strong acid salt of weakly basic drugs dissolve
more rapidly in gastric and intestinal fluids
than free bases
✓Chlorpromazine vs. chlorpromazine HCl
✓Strong acidic Cl- anion in diffusion layer ensures lower
pH than bulk
▪ Increase solubility (Cs) in diffusion layer
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• Oral administration of salt of weakly basic drugs in
solid DF generally ensures that dissolution occurs in
gastric fluid before drug passes into small intestine,
where pH conditions are unfavorable.
• Many other salt forms are increasingly being employed.
• Some salts have lower solubility & dissolution rate than
free form
o Aluminum salt of weak acids and palmoate salt of
weak bases
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• Insoluble films of aluminum hydroxide or palmitic
acid formed to coat dissolving solids when exposed
to basic or acidic environment, respectively.
• Poorly soluble salts delay absorption and may be
used to sustain release
→ Poorly soluble salt is generally employed for
suspension DFs
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• Other factors such as chemical stability,
hygroscopicity, manufacturability and crystallinity
are considered during salt selection and may
preclude choice of particular salt
• Sodium acetylsalicylate is much more prone to
hydrolysis than aspirin itself
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• One way to overcome chemical instabilities or other
undesirable features of salts is to form salt in situ or
to add basic/acidic excipients to formulation.
• Inclusion of basic ingredients aluminium
dihydroxyaminoacetate and magnesium carbonate
in aspirin tablets increase dissolution rate and
bioavailability.
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Polymorphism
• Many drugs exist in more than one crystalline
form
• Crystal habit and internal structure of
polymorphs affect physicochemical properties
✓ Melting point
✓ Density, hardness, crystal shape
✓ Solubility and dissolution rate
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• Eg., Chloramphenicol palmitate, cortisone acetate,
tetracyclines and sulphathiazole
∗ At given T and P, only one crystalline form is stable
and others are metastable.
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• Metastable tend to transform to most stable
form.
• Metastable polymorphs have higher energy and
usually lower m.pt., greater solubility and
dissolution rates.
➢One polymorph may be therapeutically active than
another!
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Chloramphenicol palmitate
• Exists in 3 crystalline forms designated A, B
and C
▪ Polymorph C is too unstable to be included in DFs
▪ Polymorph B is sufficiently stable
▪ Polymorph A is stable – therapeutically inactive
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• Bioavailability studies of oral suspensions
containing varying proportions of polymorphs
A and B investigated
❖ Extent of absorption increase in proportion of
polymorph B
❖ Rapid in vivo dissolution rate of polymorph B
❖ Polymorph A fails to produce biological effect
❑ Limit placed on content of inactive polymorph, A, in
Chloramphenicol Palmitate Mixture.
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Sulfameter (sulfamethoxydiazine)
• Exist in 6 polymorphs
• Crystalline II is about 2X as soluble as crystalline form III
• Bioavailability of form II is ~ 40 % greater than form III
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Cortisone acetate
• Found in at least 5 different forms
• Four are unstable in presence of water & change to
stable form
• Transformation of soluble metastable forms to stable
form involve appreciable caking
• Only stable form is used in suspension DFs
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Amorphous solids
• Some drugs may exist in amorphous form.
• Amorphous form usually dissolves more rapidly than
crystalline form(s).
• Significant differences in bioavailability exists b/n
amorphous and crystalline forms of drugs
(dissolution-rate limited bioavailability).
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• Novobiocin (antibiotic) - Humans and Dogs
➢ Amorphous is at least 10X more soluble than
crystalline form
➢ Amorphous form is readily absorbed from oral
suspension
➢ Crystalline form is not absorbed to any significant
extent -therapeutically ineffective
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Problem:
• Amorphous form slowly converts to more stable
crystalline form
✓Loss of therapeutic efficacy!
• Unless adequate precautions are taken to ensure
stability of amorphous form in DF, unacceptable
variations in therapeutic effectiveness may occur
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Methods of Stabilization
o Viscosity imparting agents: CMC
o Stabilizing agents: Surfactants, Polymers,…
o Add similar chemical compound
▪ Add sulfadiazine to succinylsulfathiazole suspension
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Solvates
• Many drugs can associate with solvent molecules to
produce crystalline forms known as solvates
➢When water is solvent, solvate is called hydrate!
• Solvated and non-solvated forms usually exhibit
differences in dissolution rates
➢Exhibit differences in bioavailability
• Greater solvation of crystal means lower solubility and
dissolution rate in solvent identical to solvation molecule.
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Ampicillin (antibiotic)
– anhydrous form is ~ 25% more soluble than trihydrate from
→Absorbed to greater extent from both capsule and aqueous
suspension forms than trihydrate form
Analog of Indinavir (HIV protease inhibitor)
– Anhydrous form of HCl salt has much faster dissolution rate than
dihydrate form in water
→ Anhydrous form achieves > 2X bioavailability
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• Solvate forms of drugs with organic solvents
may dissolve faster than non-solvated from
❖ Chloroform solvate of griseofulvin has greater
solubility than nonsolvated form
❖ Griseofulvin chloroformate has significantly
higher bioavailability than nonsolvated form
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Complexation
• Occur within DF and/or in GI fluids, and can be
beneficial or detrimental to absorption
• – Mucin complexes with some drugs
• →Streptomycin (antibiotic) binds to mucin, reducing
available conc. for absorption
• – Bile salts interact with neomycin, kanamycin,
nystatin to form insoluble, non-absorbable
complexes
• – Dietary components complex with tetracyclines
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• Bioavailability of drugs can be reduced by excipients
in DF
• – Dicalcium phosphate in tablet DF of tetracycline
reduces its bioavailability via formation of poorly
soluble complex
• Amphetamine and sodium CMC (thickening agent)
• – Phenobarbitone and PEG 4000 (lubricant)
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• Complexation can increase solubility of poorly soluble drugs
*Cyclodextrins
- Enzymatically-modified starches
- Composed of glucopyranose units, form ring of
– Six (α-cyclodextrin)
– Seven (β-cyclodextrin)
– Eight (γ-cyclodextrin) units
• Hydrophilic outer surface and hydrophobic inner cavity
• Lipophilic molecules fit into ring - soluble inclusion complexes
→ 1 drug molecule associate with 1 cyclodextrin molecule
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• Miconazole (antifungal) - poor solubility
→ shows poor oral bioavailability
* Solubility is enhanced by up to 55-fold and dissolution rate is
increased by 255-fold in presence of cyclodextrin
→ exhibit >2X oral bioavailability in rats
Other drugs
• Piroxicam, itraconazole, indomethacin, pilocarpine, naproxen,
hydrocortisone, diazepam and digitoxin, …
• Marketed: Itraconazole + hydroxypropyl-β-cyclodextrin
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Adsorption
• Adsorption of drug on adsorbents (kaolin, attapulgite or
charcoal) may reduce rate and/or extent of absorption
• Concurrent administration of drugs and medicines containing
adsorbents (e.g., antidiarrhoeal mixtures) result in
adsorption
→ Interfere with absorption
• Promazine-Charcoal
• Linomycin-Kaopectate (kaolin-pectin)
– Rate and/or extent of absorption depend on reversibility of
drug absorbent interaction
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• Promazine-Attapulgite / Promazine-Charcoal
− P-A dissociate readily while P-C show little tendency to
dissociate
→ Attapulgite decreases only rate but not extent of
absorption
→ Charcoal significantly reduces both rate and extent of
absorption
* Charcoal is exploited as antidote in drug intoxication!
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• Cholestyramine and colestipol are insoluble anion
exchange resins used in hypercholesterolemia
- Bind cholesterol metabolites/bile salts in intestinal
lumen and prevent the enterohepatic cycling
→ Lower serum cholesterol levels
Enterohepatic circulation
• Circulation of bile acids from liver, where they are
produced and secreted in bile, to SI, where they aid
in digestion, and back to liver
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95% of bile acids is reabsorbed in ileum
* Net effect----Each bile salt molecule is reused several
times
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• Cholestyramine reduces absorption of warfarin and
phenprocoumon (anticoagulants)
– Colestipol decreases absorption of chlorthiazide by
~50 %
• Insoluble excipients included in DFs can adsorb drugs
• Talc (glidant in tablets) adsorption cyanocobalamin
→ Interfere with absorption
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Chemical stability in GI fluids
• Instability in GI fluid is usually by acidic or enzymatic hydrolysis
• Erythromycin
– Unstable in gastric fluid
– Bioavailability improved by delaying dissolution until SI
→ Enteric coating of free base erythromycin
→ Prodrug, erythromycin stearate
∗ Passes stomach undissolved
∗ Dissolves and dissociates in intestinal fluid to yield free base
erythromycin
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• Drug dissociation
• Interrelationship b/n degree of ionization of
weak electrolyte drug and extent of
absorption is embodied in pH-partition
hypothesis
• According to pH-PH, GI epithelia act as lipid
barrier toward drugs absorbed by passive
diffusion
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• →Unionized form of weak electrolyte drugs (i.e.,
lipid-soluble form) pass across GI epithelia
• →GI epithelia is impermeable to ionized (i.e.,
poorly lipid-soluble) form of such drugs
* Absorption of weak electrolyte is determined
chiefly by extent of unionized form at site of
absorption
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• Extent to which weakly acid or base drug
ionize in solution in GI fluid is calculated using
Henderson-Hasselbalch equations.
• For weakly acidic drug:
• [HA] and [A-] are conc. of unionized and
ionized forms
• E.g., aspirin, phenylbutazone, salicylic acid
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• For weakly basic drug:
• [BH+] and [B] are conc. of ionized and
unionized forms
• E.g., chlorpromazine
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• According to equations,
- Weakly acidic drug, pKa 3.0
• → Predominantly unionized (98.4 %) in gastric fluid at pH 1.2
• → Almost totally ionized (99.98 %) in intestinal fluid at pH 6.8
- Weakly basic drug, pKa 5
• → Almost entirely ionized (99.98 %) at gastric pH of 1.2
• → Predominantly unionized (98.4 %) at intestinal pH of 6.8
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According to pH-PH
→ weakly acidic drug is more likely to be
absorbed from stomach
→ weakly basic drug from intestine
• In practice, other factors need to be taken into
consideration!
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• Limitations of pH-PH
* Extent to which drug exists in unionized form is not only factor
determining rate and extent of absorption
• Despite high degree of ionization, weak acids are well
absorbed from SI
• → Intestinal absorption of weak acid is often higher than in
stomach
• → Huge SA in SI more than compensates for high degree of
ionization
• Longer SI residence time and microclimate pH at intestinal
mucosa (lower than that of luminal pH) are thought to aid
absorption of weak acids from SI
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• Mucosal unstirred layer is not accounted for in pH-PH
- During absorption, molecules must diffuse across this
layer and then on through lipid layer
- Diffusion across this layer is significant component of
absorption process for drugs that cross lipid layer
very quickly
→ Diffusion depends on relative molecular weight
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pH-PH cannot explain why drugs (e.g., 4o NH4 cpds, TTCs) are
readily absorbed despite being ionized over entire pH of GIT
→ Ion-pair formation
* pH-PH doesn’t explain absorption of water soluble molecules by
convective flow or solvent drag
- Movement of water molecules into and out of GIT affect rate of
passage of small water-soluble molecules across GI barrier
- Absorption of water-soluble drugs is increased if water flow from
lumen to blood, provided drug and water are using same route
of absorption
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N.B. Water flow affects absorption of lipid-soluble drugs
→ Drug becomes more concentrated as water flows out of SI
→ Larger drug conc. gradient and increased absorption
Lipid solubility
• Number of drugs are poorly absorbed from GIT despite their
unionized forms predominate
• Barbiturates: Barbitone and Thiopentone
- Similar dissociation constants (pKa) 7.8 and 7.6
- Similar degrees of ionization at intestinal pH
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• Thiopentone is absorbed much better than barbitone!
→ More lipid soluble
→ Exhibit greater affinity for GI membrane
• Within homologous series, drug absorption usually increase as
lipophilicity rises
• Series of barbiturates with similar pKa (Schanker 1960)
• Hexabarbital > Secobarbital > Pentobarbital > Barbital
→ Correlation b/n Partition coefficient, P, and extent of absorption
• Measure of lipid solubility is partition coefficient, P
- Determined by drug partitioning b/n water and suitable organic
solvent at constant temperature
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• Expressed as logarithm - ratio spans several orders of
magnitude
- Octanol as organic phase
• Polar (poorly lipid soluble) (log P < 0) and relatively large
molecules such as gentamicin, ceftriaxone, heparin and
streptokinase are poorly absorbed after oral administration
→ Given by injection
• Lipid soluble drugs with favorable partition coefficients (i.e. log
P> 0) are usually absorbed after oral administration
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Improving lipid solubility
• Substituting hydrophilic by hydrophobic group
→ Clindamycin (Cl) is absorbed more than lincomycin
(OH)
• If structure cannot be modified to yield lipid
solubility, medicinal chemists may make lipid
prodrugs to improve absorption
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Molecular size and hydrogen bonding
• For paracellular absorption, mol. wt. ideally be < 200 Da
- Shape is important factor for paracellular absorption
• For transcellular passive diffusion, mol. wt. < 500 Da is
prefered
• Too many H-bonds in molecule are detrimental to
absorption
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