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Introduction of Biopharmaceutics &
Pharmacokinetics Drug Transport
What’s the plan for today
• We will look at barriers to drug entry in human body
• Close look at physiology of cell membrane
• Passage of drugs across cell membrane
• Different mechanism of drug transport
Barriers in Human body
• Our body has barriers that prevent direct entry in to blood
• Epithelia act as a barrier
• Epithelial cells cover the entire external as well as internal surface of body
• They have 2 major role
1. Protect internal environment
2. Allow exchange of nutrients, gases, solutes etc
Epithelial Tissue
Gastro-intestinal Epithelia
For drugs to be absorbed they have to
pass through biological membranes
Cell Membrane
Cross section of Intestine
Cell membrane acts as “gate Keeper”
Cell membrane plays a very important role
of controlling the movement of substance
across cell
Structure of Cell membrane
• Lipid Bilayer “fluid mosaic model”
• The cell membrane consists double
layer of amphipathic phospholipids
• Hydrocarbon chains face inwards,
polar heads face outside
• Create a inner hydrophobic core &
outside hydrophilic
Cell Membrane: “Fluid Mosaic Model”
• Attached to lipids are
proteins
• Membrane is dynamic with
changing composition of
lipids and proteins
• Crystalline solid-liquid
state
Composition of cell membrane
Lipids
• Phospholipids,
glycolipids, and sterols
• The entire membrane is
held together via noncovalent interaction of
hydrophobic tails
Carbohydrates
• Mostly found on outer
surface
• Glyco+proteins
• Glyco+lipids
• Short polysaccharides
forming a cell coat
Proteins
• 50% of membrane
volume
• Important different
functions
• cell–cell contact, surface
recognition,
cytoskeleton contact,
signaling, enzymatic
activity, or transporting
substances across the
membrane
Role of Proteins in Cell Membrane
• Structural Role
• Link cytolskeleton to membrane
• Cell to Cell connections
• Act as enzymes, catalyse reactions near cell membrane
• Receptors
• These receptors sense specific signals
• Transporters
• Channels
• Act as carrier
How are drugs transported across cell
membrane ?
Two major mechanism by which the drugs are transported across cell membrane
TRANSCELLULAR
(INTRA)
Transport ACROSS the membrane
PARACELLULAR
(INTER)
Transport BETWEEN the membrane
cells
Classification of Trans-cellular Pathway
TRANSCELLULAR
PASSIVE TRANSPORT
Transport ACROSS the membrane
ACTIVE TRANSPORT
PASSIVE TRANSPORT
PASSIVE
DIFFUSION
PORE
TRANSPORT
ION PAIR
TRANSPORT
FACILITATED OR
MEDIATED
DIFFUSION
Passive Diffusion
• Movement of drugs across membrane
• Driving force to move drug is concentration
difference across cell membrane
• Also called Non-ionic diffusion
• Almost 90% of drugs absorbed by passive diffusion
Passive Diffusion
• Passive diffusion best explained by “Ficks 1st Law of diffusion”
• Drug molecule diffuse from a region of higher concentration to one of lower
concentration until equilibrium is attained and
• that the rate of diffusion is directly proportional to the concentration
gradient across the membrane
Ficks
st
1
law of Diffusion
• Mathematically
𝑑𝑄
•
𝑑𝑡
•
•
•
•
•
•
=
𝐷𝐴𝐾𝑚 𝑤
/
ℎ
𝐶𝑔𝑢𝑡 − 𝐶
Where
𝑑𝑄
= Rate of diffusion
𝑑𝑡
D = diffusion coefficient, A = area of absorbing membrane
Km/w = Partition coefficient (Lipoidal membrane/Aq water)
𝐶𝑔𝑢𝑡 − 𝐶 = concentration difference across cell membrane
h = thickness of membrane
Ficks
𝑑𝑄
•
𝑑𝑡
=
st
1
law of Diffusion
𝐷𝐴𝐾𝑚 𝑤
/
ℎ
𝐶𝑔𝑢𝑡 − 𝐶
• Based on the Fick’s law, what general conclusions can we say for
Passive diffusion of Drugs ??
Ficks
•
𝑑𝑄
𝑑𝑡
•
𝑑𝑄
𝑑𝑡
•
𝑑𝑄
𝑑𝑡
=
st
1
law of Diffusion
𝐷 𝐴 𝐾𝑚 𝑤
/
ℎ
𝐶𝑔𝑢𝑡 − 𝐶
Under usual conditions,
these are all constants
= 𝑃 𝐶𝑔𝑢𝑡 − 𝐶 , where P is permeability coeff (ease with which
drug moves across membrane)
= 𝑃 𝐶𝑔𝑢𝑡 under sink conditions 𝐶𝑔𝑢𝑡 >> 𝐶
• Diffusion is a 1st order process
Pore Transport
Other Names:
Convective, bulk flow, filtration
• Transport through protein channels
• Driving force is hydrostatic pressure or osmotic
that leads to water flow
• Small solute molecule move along water (solvent
drag)
• Which drugs use this pathway
•
•
•
•
Low molecular weight (<100)
Low molecular size
Water soluble drugs through aqueous filled channels
Ex. Urea, Water, sugars
Ion-Pair transport
Endogenous
anion
-
+
Neutral complex
-
Membrane
+
+
-
+
Cationic
drug
-
• Drugs that are ionized under
all pH
• Combine with endogenous
ions at GIT (Mucin)
• Form reversible-neutral
complex
• Complex sufficiently lipophilic
• Passive diffusion occurs
• After crossing, drugs
dissociate
• Ex. Propranolol
“Carrier” Mediated Transport (Features)
• Specialized transport mechanism
• Transport done by Special Proteins
• Transport proteins have non-polar region on the
outside as a result they can merge with membrane
lipids
• Binds to drug (non-covalent forces) & transport
across the membrane
“Carrier” Mediated Transport
Most of vitamin B group is transported by carrier proteins.
Does it make sense to prescribe a SINGLE LARGE dose of
these vitamins ????
Rate of
Diffusion
• Move in both directions
• “Structure specific” binding of substrates
by proteins
• Process is capacity limited
• Competitive process since transporters
limited
Drug Conc
“Carrier” Mediated Transport
• Carrier mediated transport can be used to transport drugs as well
• Drugs similar to “internal Substrates” are also transported by proteins
• Anti-cancer drugs such as 5-FU, 5-BU are transported by this
mechanism
• Important mode of transport for Monosacharides, amino acids,
vitamins
“Carrier” Mediated Transport
Is Energy Involved in Transport ??
NO
Facilitated Diffusion
YES
Active Transport
“Carrier” Mediated Transport
Facilitated Diffusion
• Carrier proteins move substance along the concentration
gradient
• NO energy is involved
• Driving force is concentration gradient
• Process not inhibited by chemicals blocking energy production
• Limited importance for transport of drugs
• Examples:
• Entry of glucose in to RBC
• Intestinal absorption of Vitamin B1, B2
• Intrinsic factor (Transporter glycoprotein secreted by
stomach) complex with B12, transported across intestine
“Carrier” Mediated Transport
Is Energy Involved in Transport ??
YES
NO
Facilitated
Diffusion
Active Transport
YES
Primary Active
Transport
Is ATP directly
needed for
transport ??
NO
Secondary Active
Transport
“Primary” Active Transport
• Primary active transport use ATP energy to move substances across membrane
• Move only in one direction (uniporter)
“Primary” Active Transport
• Primary active transport use ATP energy to move substances across membrane
• Move only in one direction (uniporter)
• ABC (ATP-binding cassette) Transporters
•
•
•
•
•
Mechanism to protect from outside molecules
Transport small molecules (Drugs & toxins)
Mostly efflux out of cells
P-glycoprotein well known efflux transporter
Known to efflux drugs out leading to drug resistance
“Active Transporters”
Active Transport Features
• Molecule transported against concentration gradient
• Need energy to transport (typically provided by ATP)
• Process is faster that passive diffusion
Endogenous molecules Transported
• Na, K, Fe
• Glucose
• Certain Amino Acids
Drugs Transported by Active route
• 5-FU, 5-BU via pyrimidine transport
• Methydopa, levodopa via Amino
acid transporter
• Enalapril via peptide transporter
“Carrier” Mediated Transport
Is Energy Involved in Transport ??
YES
NO
Facilitated
Diffusion
Active Transport
YES
Primary Active
Transport
Is ATP directly
needed for
transport ??
NO
Secondary Active
Transport
“Secondary” Active Transport
Driving ion
Driven ion
• No Direct requirement of ATP
energy
• Energy obtained from moving
“driving ion” along conc
gradient
• Movement of “driven” or
“passenger ion” can either
direction
“Secondary” Active Transport
• SYMPORT
• Direction of Driving & Driven ion is same
• Ex. Na+/glucose cotransporter (SGLT1),
found in the small intestine and kidney
proximal tubules, simultaneously
transports 2 Na+ ions and 1 glucose
molecule into the cell across the plasma
membrane
• Transporter uses the conc gradient energy
of Na to move glucose against conc
gradient
New Drugs developed that inhibit “Secondary Active
Transport”
FORXIGA® in Type 2 diabetes
FORXIGA® is indicated in adults aged 18 years and older
with Type 2 diabetes mellitus to improve glycaemic
control as:
Monotherapy: When diet and exercise alone do not provide adequate glycaemic control in patients for
whom use of metformin is considered inappropriate due to intolerance.
Add-on combination therapy: In combination with other glucose-lowering medicinal products
including insulin, when these, together with diet and exercise, do not provide adequate glycaemic
control.
FORXIGA® is not indicated for the management of obesity or high blood pressure. The use of FORXIGA® with pioglitazone is not
recommended. FORXIGA® has not been studied in combination with glucagon-like peptide-1 analogues.
Reference:
1. FORXIGA®. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2013.
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© 2014 Bristol-Myers Squibb | Last updated: January 2014 | 732HQ13PR09408
“Secondary” Active Transport
• ANTI-PORT
• If direction of Driving & Driven ion is
OPPOSITE
• Ex. Na+/Ca2+ exchanger (NCX), found in
cardiac muscle cells and elsewhere
• Transports 3 Na+ ions into the cell in
exchange for 1 Ca2+ion transported out
of the cell
How are drugs transported across cell
membrane ?
Two major mechanism by which the drugs are transported across cell membrane
TRANSCELLULAR
(INTRA)
Transport ACROSS the membrane
PARACELLULAR
(INTER)
Transport BETWEEN the membrane
cells
Paracellular Transport
PARACELLULAR
(INTER)
Transport BETWEEN the membrane
cells
• Transport of drugs through the junctions
between the GI epithelial cells
• Which drugs ??
• Only for Small molecules
• Mostly for lipophilic drugs
• Tight junctions are negatively charged & prefer
positive charged molecules
Paracellular Transport
• Two major mechanism of transport between the cells
1. Transport BETWEEN the membrane cells
Tight Junctions
2. Transport BETWEEN the membrane cells
at temporary opening due to shedding of
cells (Persorption)
Paracellular Transport
Can we modify these tight junctions
to increase drug transport ???
Transport BETWEEN the
membrane cells
Endocytosis, Vesicular Transport
• Transport by engulfing extracellular material & forming
vesicle
• Energy dependent process
• Trans-cellular route
• Phagocytosis (cell eating) is for solid particulates
• Pinocytosis (cell drinking) is for liquids
• Examples:
• Macromolecules : Starch, fats
• Oil soluble vitamins
• Drugs such as Insulin
Summary of Different Transport Process
Passive Diffusion
Drugs with high lipophilicity, Most drugs use this mechanism
(100-400 MW range)
Pore Transport
Water soluble drugs (<100 MW)
Ion-Pair transport
Drugs that ionize at all pH, complex with other ions, gets
transported
Carrier mediated
Structure specific transport by specific proteins from specific
sites rich in these proteins
Endocytosis
Macromolecular drugs (large drugs) and nutrients
Single drug can be transported by multiple mechanism for ex, Vitamins are transported
by passive diffusion as well as carrier mediated process
Road to systemic circulation for Oral drugs
• Hepatic portal vein carries blood from GI tract
to liver
• Drug undergoes first pass metabolism before
entering general circulation
• Minor lymphatic pathway for substances
absorbed at GI
• More important for large molecules (>10,000
Da)
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