TRANSPORT TRANSMEMBRAN

FAKULTAS FARMASI UNIVERSITAS

JEMBER
 Absorption of Drugs
• Drugs can exert their pharmacologic action only
when they come into blood circulation from their site
of application (absorption).
• There always exist a correlation between the plasma
concentration of a drug and the therapeutic
response.
• Drugs that have to enter the systemic circulation to
exert their effect can be administered by three major
routes:
– The enteral routes
– The parenteral route
– The topical route
 Systemic Absorption is Dependent of:

• The anatomy and physiology of the drug

absorption site.
• The physicochemical of drug.
• The nature of drug product/formulation
factors
 Physiological Factors Affecting Oral
Absorption
• Physiological Factors
A. Membrane physiology
 Considering the structure of membranes
 Transport processes
B. Gastrointestinal physiology
 Characteristics of gastrointestinal physiology
 Gastric motility & emptying
 Influence of food
 Structure and physiology of cell
membrane for absorption
• For drug to be absorbed, it must pass through
biological membranes.

Davson-Danielli Model
Fluid mozaik model by Singer & Nicholson
 CELL MEMBRANE
• Also called the plasma membrane, plasmalemma or
phospholipid bilayer.
• The plasma membrane is a flexible yet sturdy barrier that
surrounds & contains the cytoplasm of a cell.
• Cell membrane mainly consists of:
1. Lipid bilayer-
-phospholipid
-Cholesterol
-Glycolipids.
2. Proteins-
-Integral proteins
-Lipid anchored proteins
-Peripheral Proteins

8
Phospholipid
Cholesterol
 GLYCOLIPIDS
• Carbohydrate chains attached to a phospholipid
head
• Functions:protective, site of receptor binding
 PROTEINS
• Integral protein Functions:
• lipid anchored protein
• peripheral protein
– channel for molecules
in/out of cell
– carriers for selective
molecule in/out of cell
– catalyzes reaction on the
surface
– receptor for hormon
binding
 Membrane Function
 Membranes organize the chemical activities of cells.
 The outer plasma membrane
 forms a boundary between a living cell and its

surroundings
 Exhibits selective permeability

• Controls traffic of molecules in and out

 Passage of Drugs Across Cell Membranes

• For systemic absorption, a drug must pass from the

absorption site through or around one or more layers
of cells to gain access into the general circulation.
• The permeability of a drug at the absorption site into
the systemic circulation is intimately related to the
molecular structure of the drug and the physical and
biochemical properties of the cell membranes.
• For absorption into the cell, a drug must tranverse the
cell membrane. Transcellular absorption is the process
of a drug movement across a cell.
Nature of The Drug Transport in The Body

• Transcellular transport
• Paracellular transport
 Example of Some Membran Types

A. Blood brain barrier

B. Renal tubules
C. Blood capillaries and renal gromelural
membranes
 Transcellular Transport of Substances
Across the Plasma Membrane (PM)
1. Passive diffusion
2. Pore transport
3. Facilitated diffusion
4. Active transport
5. Ionic or electrohemical diffusion
6. Ion-pair transport
7. Endocytosis
 Passive Diffusion
• Also called nonionic diffusion.
• It is the major process for absorption of more than
90% of the drugs.
• The driving force is concentration gradien.
• No energy source is required.
• Best expressed by Fick’s first law of diffusion.
dQ/dt = {DAK/h}(CGI - Cp)
where dQ/dt = rate of diffusion; D = diffusion coefficient; K = partition
coefficient; A = surface area of membrane; h = membrane thickness; and CGI - Cp
= difference between the concentrations of drug in the GI tract and in the
plasma.
Characteristics of Passive Diffusion
• Passive diffusion:
– Energy independent
– Nonsaturable
– Molecular weight of drugs between 100-400
Dalton.
– Follows first order kinetics.
– Sink condition is maintained (Cp << 10%)
• DAK/h = P (permeability)
• dQ/dt = PCGI
 Stokes-Einstein equation

D = (k T) / (6 π η a)

D = Diffusion coefficient (cm2/s)

k = Boltzmann’s constant
T = Temperature (oK)
η = (kinematic) viscosity
a = molecular size
 Factors Affecting Diffusion Rate
 Steepness of
concentration gradient
 Steeper gradient, faster
diffusion
 Molecular size
 Smaller molecules,
faster diffusion
 Temperature
 Higher temperature,
faster diffusion
 Pore Transport
• It is also called as convective transport/filtration.
• For low molecular weight drug (< 100 Dalton),
generally water soluble drugs.
• The driving force is hydrostatic pressure or osmotic
difference across the membrane.
 Carrier Mediated Transport
• The mechanism is involving a membrane component
called as the carrier and binding reversibly with the
molecules to be transported.
• Characteristics of carrier mediated transport are:
– Structure specific.
– Nutrients and false nutrients absorbed by the same carrier.
– The number of carriers are limited.
– Competition between agents with similar structure.
– Since the number of carriers is limited, the system
becomes saturated.
– Occurs in specific sites of intestinal tract which are rich in
number of carriers.
 Facilitated Diffusion
• Carrier mediated transport system that operates
down the concentration gradient.
• More faster than passive diffusion.
• Less important in the absorption of drugs
• An intrinsic factor (IF) forms a complex with vitamin
B12.
• Glucose enter/leaves cells through facilitated
diffusion; three glucose uniporters, GLUT1, GLUT3,
and GLUT4, are found in nearly every tissue and have
a high affinity for glucose; GLUT2, which is found in
tissues carrying large glucose fluxes (such as
intestine, kidney, and liver).
 Active Transport
• Active transport more important than facilitated
diffusion.
• Against the concentration gradien (uphill transport).
• Energy is required, can be inhibited by metabolic
poison that interfere energy production.
 Efflux of Drug From Intestine
• Counter transport efflux proteins that expel spesific
drugs back into the lumen of GIT after they have
been absorbed.
• Ex: P-glycoproteins
• Requires energy
• Against a concentration gradient
• Competitively inhibited by structural analogues or
metabolism inhibitors
• Saturable process
• The normal physiological role of P-gp is detoxification
through active secretion of xenobiotics.
 Role of P-gp in Cancer

• Approximately 50% of human cancers express P-gp at

levels sufficient to confer MDR.
• In some cancers inhibite P-gp improved response to
chemotherapy.
• Multi drug resistance (MDR) is the phenomenon
whereby cancer cells develop resistance to cytotoxic
drugs.
• MDR is a result of over expression of P-gp.
• P-gp utilize ATP hydrolysis to pump drugs out of cells.
 Ionic or Electrochemical Diffusion
• The charge of membrane influence the permeation
of drugs.
• The rate of permeation: unionized molecules >
anions > cations.
• Such a drug is moving downhill with electrical
gradient.
 Ion-Pair Transport
• Transport of ionize drugs
• Forming reversible neutral complexes with
endogenous ions of the GIT like mucin.
 Endocytosis
• Engulfing extracellular materials by forming a vesicle.
• Important for the cellular uptake of fat, starch, oil
soluble vitamin, sabin polio vaccine, and insulin.
• Drug is absorbed into lymphatic circulation (by pass
hepatic metabolism)
• Endocytosis can occur in three ways:
• Phagocytosis ("cell eating")
• Pinocytosis ("cell drinking")
• Receptor-mediated endocytosis
 Paracellular Transport

• Water and small hydrophylic molecules pass through

numerous aqueous pores.
• Transport of material across aqueous pores between the
cells
• The cells are joined together via closely fitting tight
junctions on their apical side.
• Important for the transport of ions, sugars, amino acids
and peptides at concentration above the capacity of their
carriers.
• Small, hydrophilic and charged drugs.
• Molecular weight cut-off:200Da
The Mechanism of Paracellular Transport

• Filtration: across capillary wall

• Bulk Flow: transfer of solutes across
membranes by osmotically driven water
 Pertanyaan Tugas
1. Definisikan tentang absorbsi obat ! Rute apa sajakah yang
memungkinkan obat dapat diabsorbsi dan menimbulkan efek ?
2. Apa yang anda ketahui tentang sink conditions ? bagaimanakah
kondisi sink dapat dipertahankan sehingga terjadi absorbsi komplit
obat dalam GIT ?
3. Mengapa pemberian vitamin B disarankan dalam dosis kecil
berulang daripada dosis besar tunggal ?
4. Jelaskan persamaan dan perbedaan difusi pasif dengan difusi
terfasilitasi ?
5. Mengapa transport aktif bukan mekanisme absorbsi utama obat ?
Bagaimana absorpsi molekul nutrient analog seperti
antineoplastik ?