TranslocationTranslocation of of drug Molecules drug Molecules

acrossacross Cell Cell MembraneMembrane

Dr. Ali Ahmed Dr. Ali Ahmed SheraziSherazi

Cell Membrane

Point #2 and Point #3Point #2 and Point #3

Repeat the four-step process under Repeat the four-step process under Point #1.Point #1.

Classification of Classification of Translocation of drug Translocation of drug

moleculesmoleculestranslocation

1. Simple transfer 2. Specialized transport

diffusion filteration Active transport Facilitated transport pinocytosis

primary secondary

Co transport Counter transport

A membrane’s molecular A membrane’s molecular organization results in organization results in selective permeabilityselective permeability

A steady traffic of small molecules and ions moves A steady traffic of small molecules and ions moves across the plasma membrane in both directions.across the plasma membrane in both directions. For example, sugars, amino acids, and other nutrients For example, sugars, amino acids, and other nutrients

enter a muscle cell and metabolic waste products leave.enter a muscle cell and metabolic waste products leave. The cell absorbs oxygen and expels carbon dioxide.The cell absorbs oxygen and expels carbon dioxide. It also regulates concentrations of inorganic ions, like It also regulates concentrations of inorganic ions, like

NaNa++, K, K++, Ca, Ca2+2+, and Cl, and Cl--, by shuttling them across the , by shuttling them across the membrane.membrane.

However, substances do not move across the barrier However, substances do not move across the barrier indiscriminately; membranes are selectively indiscriminately; membranes are selectively permeable. permeable.

Permeability of a molecule through a membrane Permeability of a molecule through a membrane depends on the interaction of that molecule with the depends on the interaction of that molecule with the hydrophobic core of the membrane.hydrophobic core of the membrane. Hydrophobic molecules, like hydrocarbons, COHydrophobic molecules, like hydrocarbons, CO22, and O, and O22, ,

can dissolve in the lipid bilayer and cross easily.can dissolve in the lipid bilayer and cross easily.

A membrane’s molecular A membrane’s molecular organization results in organization results in selective permeabilityselective permeability

Ions and polar molecules pass through Ions and polar molecules pass through with difficulty.with difficulty.

This includes small molecules, like water, This includes small molecules, like water, and larger critical molecules, like glucose and larger critical molecules, like glucose and other sugars.and other sugars.

Proteins can assist and regulate the Proteins can assist and regulate the transport of ions and polar molecules.transport of ions and polar molecules.

A membrane’s molecular A membrane’s molecular organization results in organization results in selective permeabilityselective permeability

Specific ions and polar molecules can cross the Specific ions and polar molecules can cross the lipid bilayer by passing through lipid bilayer by passing through transport transport proteinsproteins Some transport proteins have a hydrophilic Some transport proteins have a hydrophilic

channel to which certain molecules or ions can channel to which certain molecules or ions can use as a tunnel through the membrane.use as a tunnel through the membrane.

Others bind to these molecules and carry their Others bind to these molecules and carry their passengers across the membrane physically.passengers across the membrane physically.

Each transport protein is specific as to the Each transport protein is specific as to the substances that it will translocate (move).substances that it will translocate (move). For example, the glucose transport protein in the For example, the glucose transport protein in the

liver will carry glucose from the blood to the liver will carry glucose from the blood to the cytoplasm, but not fructose, its structural isomer. cytoplasm, but not fructose, its structural isomer.

Drug Translocation Drug Translocation MechanismsMechanisms

Passive TransportPassive Transport Simple DiffusionSimple Diffusion Facilitated DiffusionFacilitated Diffusion

Active TransportActive Transport Primary Active TransportPrimary Active Transport Secondary Active TransportSecondary Active Transport

Co-TransportCo-Transport Counter TransportCounter Transport

EndocytosisEndocytosis PinocytosisPinocytosis Receptor-Mediated EndocytosisReceptor-Mediated Endocytosis PhagocytosisPhagocytosis

Factors Affecting Factors Affecting TranslocationTranslocation

Physico-Chemical Properties of Physico-Chemical Properties of DrugsDrugs SolubilitySolubility

Hydrophilic-Water LovingHydrophilic-Water Loving Lipophilic-Lipid LovingLipophilic-Lipid Loving

Size & Shape of Drug MoleculeSize & Shape of Drug Molecule Ionization Constant or PkIonization Constant or Pka a Value of DrugValue of Drug

Passive TransportPassive Transport1. Simple Diffusion/Passive Diffusion1. Simple Diffusion/Passive Diffusion

It is the movement of drug molecules from an It is the movement of drug molecules from an area of higher concentration toward the low area of higher concentration toward the low concentration through a bio-membrane.concentration through a bio-membrane.

In the absence of other forces, a substance will In the absence of other forces, a substance will diffuse from where it is more concentrated to diffuse from where it is more concentrated to where it is less concentrated, down its where it is less concentrated, down its concentration gradientconcentration gradient..

The diffusion of a substance across a biological The diffusion of a substance across a biological membrane is membrane is passive transportpassive transport because it because it requires no energy from the cell to make it requires no energy from the cell to make it happen.happen. The concentration gradient represents The concentration gradient represents

potential energy and drives diffusion.potential energy and drives diffusion.

Passive TransportPassive Transport1.1. Simple Diffusion/Passive DiffusionSimple Diffusion/Passive Diffusion

However, because membranes are However, because membranes are selectively permeable, the selectively permeable, the interactions of the molecules with the interactions of the molecules with the membrane play a role in the diffusion membrane play a role in the diffusion rate.rate.

Diffusion of molecules with limited Diffusion of molecules with limited permeability through the lipid bilayer permeability through the lipid bilayer may be assisted by transport may be assisted by transport proteins. proteins. ((Facilitated DiffusionFacilitated Diffusion))

1. Diffusion Process

Example:Example:•Lipid soluble substancesLipid soluble substances•Unionized (un dissociated) Unionized (un dissociated) drugsdrugs

• Doesn’t require energyDoesn’t require energy• Moves high to low concentrationMoves high to low concentration Example: Example: •Oxygen or water diffusing into a Oxygen or water diffusing into a cell cell •Carbon dioxide diffusing outCarbon dioxide diffusing out.

Diffusion will depend upon the Diffusion will depend upon the following factors.following factors.

1. Surface area to which drug is 1. Surface area to which drug is exposed. exposed.

2. Cross section or thickness of 2. Cross section or thickness of the membrane.the membrane.

3. Time period for which diffusion 3. Time period for which diffusion is taking place. is taking place.

Passive TransportPassive Transport

2. Facilitated Diffusion2. Facilitated Diffusion Many polar molecules and ions that are normally impeded Many polar molecules and ions that are normally impeded

by the lipid bilayer of the membrane diffuse passively with by the lipid bilayer of the membrane diffuse passively with the help of the help of transport proteinstransport proteins that span the membrane. that span the membrane.

The passive movement of molecules down its The passive movement of molecules down its concentration gradient via a transport protein is called concentration gradient via a transport protein is called facilitated diffusionfacilitated diffusion..

Transport proteins have much in common with enzymes.Transport proteins have much in common with enzymes. They may have specific binding sites for the solute.They may have specific binding sites for the solute. Transport proteins can become saturated when they Transport proteins can become saturated when they

are translocating passengers as fast as they can.are translocating passengers as fast as they can.

Passive TransportPassive Transport 2.Facilitated Diffusion2.Facilitated Diffusion

While transport proteins do not usually catalyze While transport proteins do not usually catalyze chemical reactions, they do catalyze a chemical reactions, they do catalyze a physicalphysical process, transporting a molecule across a process, transporting a molecule across a membrane that would otherwise be relatively membrane that would otherwise be relatively impermeable to the substrate.impermeable to the substrate...

Passive TransportPassive Transport 2.Facilitated Diffusion

Energy independent (passive process)Energy independent (passive process) Speedy than diffusionSpeedy than diffusion Structure specificStructure specific SaturableSaturable

EXAMPLESEXAMPLES

Entry of glucose into RBCsEntry of glucose into RBCs

Intestinal absorption of vitamins Intestinal absorption of vitamins BB11,B,B22,B,B1212

Active TransportActive Transport Some facilitated transport proteins can move solutes Some facilitated transport proteins can move solutes

against their concentration gradient, from the side against their concentration gradient, from the side where they are less concentrated to the side where they where they are less concentrated to the side where they are more concentrated.are more concentrated.

This This active transportactive transport requires the cell to expend its requires the cell to expend its own metabolic energy.own metabolic energy.

Active transport is critical for a cell to maintain its Active transport is critical for a cell to maintain its internal concentrations of small molecules that would internal concentrations of small molecules that would otherwise diffuse across the membrane.otherwise diffuse across the membrane.

Active transport is performed by specific Active transport is performed by specific proteins embedded in the membranes.proteins embedded in the membranes.

ATP supplies the energy for most active ATP supplies the energy for most active transport.transport. Often, ATP powers active transport by shifting a Often, ATP powers active transport by shifting a

phosphate group from ATP (forming ADP) to the phosphate group from ATP (forming ADP) to the transport protein.transport protein.

This may induce a conformational change in the This may induce a conformational change in the transport protein that translocates the solute across transport protein that translocates the solute across the membrane.the membrane.

Active TransportActive Transport Energy dependentEnergy dependent Against concentration gradient Against concentration gradient

(up hill movement)(up hill movement) Carrier is utilizedCarrier is utilized Structure specificity is required Structure specificity is required Saturable processSaturable process Limited to certain sitesLimited to certain sites

TYPESTYPES1.Primary active transport1.Primary active transport2.Secondary active transport2.Secondary active transport

Active TransportActive Transport1. Primary Active Transport1. Primary Active Transport

One substance combines with one One substance combines with one carrier and the energy produced by carrier and the energy produced by the hydrolysis of ATP is used to the hydrolysis of ATP is used to move substance against conc. move substance against conc. Gradient. Gradient. Example:

In plants, bacteria, and fungi, a proton pump is the major electrogenic pump, actively transporting H+ out of the cell.

Active TransportActive Transport2. Secondary Active Transport2. Secondary Active Transport

Two solutes share a common carrier Two solutes share a common carrier ,out of which one is driving solute ,out of which one is driving solute and other is actual substrate that is and other is actual substrate that is transported.transported.

Examples: Pumping Na+ (sodium ions) out and K+

(potassium ions) in against strong concentration gradients. Called Na+-K+ Pump

Active TransportActive Transport2. Secondary Active Transport2. Secondary Active Transport

Active Transport2. Secondary Active Transport2. Secondary Active Transport

TYPESTYPES

a. Co-transport or Symporta. Co-transport or Symport

Same directionSame direction

e.g. H / Sucrose Cotransportere.g. H / Sucrose Cotransporter

b. Counter Transport or Antiportb. Counter Transport or Antiport

opposite directionopposite direction

e.g. Na/Ke.g. Na/K

EndocyosisEndocyosis1. Pinocytosis1. Pinocytosis

PinocytosisPinocytosisEngulfing extra cellular materials within a Engulfing extra cellular materials within a segment of the cell membrane to form segment of the cell membrane to form saccules or vesicles, then pinched off saccules or vesicles, then pinched off intracellularly and transported across cell intracellularly and transported across cell membrane where they released engulfed membrane where they released engulfed materialmaterial

Energy dependentEnergy dependent Structure. specificityStructure. specificity Saturable process Saturable process Competitive in natureCompetitive in nature

Examples: Fats, starch, Proteins

insulin, Polio Vaccine

EndocytosisEndocytosis2. 2. Receptor-Mediated EndocytosisReceptor-Mediated Endocytosis

Receptor-mediated endocytosisReceptor-mediated endocytosis is very is very specific in what substances are being specific in what substances are being transported.transported.

Receptor-mediated endocytosis enables a cell to Receptor-mediated endocytosis enables a cell to acquire bulk quantities of specific materials that acquire bulk quantities of specific materials that may be in low concentrations in the environment.may be in low concentrations in the environment. Human cells use this process to absorb Human cells use this process to absorb

cholesterol.cholesterol.

EndocytosisEndocytosis3. Phagocytosis

PhagocytosisPhagocytosis One type of endocytosis is One type of endocytosis is PhagocytosisPhagocytosis, ,

“cellular eating”.“cellular eating”. In Phagocytosis, the cell engulfs a particle by In Phagocytosis, the cell engulfs a particle by

extending pseudopodia around it and packaging extending pseudopodia around it and packaging it in a large vacuole.it in a large vacuole.

The contents of the vacuole are digested when The contents of the vacuole are digested when the vacuole fuses with a lysosome.the vacuole fuses with a lysosome.

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Thanks for the Patience.Thanks for the Patience.