UNIT I

MECHANISMS
OF
DRUGPERMEATION/TRANSPORT

S. SANGEETHA., M.PHARM., (Ph.d)

Department of Pharmaceutics
SRM College of Pharmacy
SRM University
Mechanismsofdrugpermeation
Permeation: isthemovementofdrugmoleculesin
to&withinthebiologicalenvironment.Itinvolves
severalprocessesofdrugtransportacrossthecell
membranes.
 Generallythedrugsareadministeredaway
fromtheirsiteofaction.
Toreachtheirsiteofactiontheyare
permeatefromonecompartmentto
anotherbycrossingthedifferentbarriers.
Sothedrugshavetocrossthecell
membranes.
Examples:
 Cellmembrane:

Fluidbilayerofphospholipids.
Scatteredmembraneproteinmoleculesembeddedinbilayerserveas
Receptors selectivetargetsfordrugaction
Ionchannels
Transporters
Lipidmoleculesarecapableoflateralmovement.
Itisflexible
Hashighelectricalresistance
Relativelyimpermeabletohighlypolarmolecules
Highlypermeabletolipidsolubledrugmolecules
CELLMEMBRANE
 MainMechanismsOfDrugPermeation/Transport
1.Passivediffusion
Lipiddiffusion
Aqueousdiffusion
2.Carriermediatedtransport
Activetransport
Facilitateddiffusion
3.Pinocytosis
Endocytosis
Exocytosis
 PassiveDiffusion
Drugs cross the cell membranes along the concentration
and electrical gradient without expenditure of energy according
to Ficks Law.
Ficks Law:
Flux(moleculesperunittime)=(C1 C2)xAreaxPermeabilityCoefficient
Thickness
PermeabilityCoefficient:
Itisameasureofthemobilityofthedrugmoleculesinthe
mediumofdiffusionpath.
 Lipid diffusion
The most important mechanism for transport of majority
of drugs in the body. It is the passive movement of lipid
soluble molecules through membranes or other lipid
structures.
CharacteristicsofLipidDiffusion:
Passiveprocess,governedbyFicks Law.
Alongaconcentrationgradient.
Onlylipidsolubledrugmoleculescancross.
Itoccursthroughthecells,bydissolvinginthelipidmatrixof
themembrane.
Energynotrequired.
Notsaturable orcapacitylimited
Notinhibitable byothersubstances.
Example: Mostofthedrugs
 FactorsAffectingtheLipidDiffusion
1. ConcentrationgradientFromhigherlower
2. SurfaceAreaLargertheSAgreaterthediffusion
3. LipidsolubilityThemostimportantfactor.Itisdependentupon:
a) Lipidaqueouspartitioncoefficient.
b) Degreeofionization.Itdependson
pKaofdrug(Ionizationconstant)
pHofthemedium.
Lipidaqueouspartitioncoefficient
Itdetermineshowreadilythedrugmoleculescanmovebetween
aqueous&lipidmedia,.
GreaterthecoefficientFasterthediffusion
DegreeofIonization :Itdependson
pKa ofadrug: WhenpHissameaspKa ,50%drugisionizedand
50%isunionized.
Aspirin3.5,Morphine7.9
pHofthemedium:IonizationofweakelectrolytesispH
dependent.
Ionizationofweakelectrolytedrugs(weakacidicorweakbasic)
ispHdependent,theylose/gainprotonsasfollows:
Weakacidicdrug:
Neutralaspirin Aspirinanion+Proton
_
HA A +H+
weakbasicdrug:
Pyrimethamine cation NeutralPyrimethamine +Proton
BH+ B +H+
AtlowpH Reactionmovestowardsleft
AthighpH Reactionmovestowardsright
SoWeakAcidicdrugsaremostlynonionizedatlowpH &
weakbasicdrugsarenonionizedathighpHorviceversa.
 Non - nionized drug: Ionized drug:
Uncharged , Non polar Charged , Polar
Lipid soluble Lipid insoluble, Water soluble
Permeates membrane rapidly Does not permeates rapidly by
by lipid diffusion. lipid diffusion

Ionization lipid solubility so Permeable form of a drug is

determined by relative concentration of its Ionized & Non -ionized
forms
 ThisrelationshipisgivenbyHENDERSONHASSELBALCHEQUATION as
Log(Protonated) =pKa pH
(Unprotonated)

Foracids:pKa =pH+log[HA] Or MolecularConc.OfNonIonizedacid

[A ] MolecularConc.OfIonizedacid
Forbases:pKa =pH+log[BH+] OrMolecularConc.OfIonizedbase
[B] MolecularConc.OfNonIonizedbase
_
If[A ]=[HA]then[HA]=1
_
[A ]
Sincelog1is0,underthisconditionpKa =pH
 Sowhen pKa =pH, 50%drugisionized&50%isNon
ionized ratiois 1/1
onedegreechangeinpHaltersunionized:ionized,10
folds.
pH Weak acidic drugs Weak basic drugs
Un-ionized : ionized Un-ionized : ionized
=pKa -3 units 1:0.0001 1:1000
=pKa-2 units 1:0.001 1:100
=pKa-1 unit 1:0.01 1:10
=pKa 1:1 1:1
=pKa + 1 unit 1:10 1:0.01
=pKa + 2 units 1:100 1:0.001
=pKa + 3 units 1:1000 1:0.0001
Q: Aspirin is a weak organic acid with a pKa of 3.5. What
percentage of a given dose will be in the lipid-soluble
form in the duodenum at a pH of 4.5 ?
a) About 1%
b) About 10%
c) About 50%
d) About 90%
e) About 99%
 ImportantimplicationsofHHErelationshipare:
1. Enhancingtheurinaryexcretionofweakelectrolytes.
2. Iontrapping/pHpartition.
1. ManipulationofpHofurinecanhelpinenhancingurinary
excretionofdrugsincaseofoverdosage.
Weakacidsareexcretedfasterinalkalineurine
Weakbasesareexcretedfasterinacidicurine.
Alkalinization ofurinewithSodiumbicarbonatecanpromote
excretionofweakacidicdrugsi.e Aspirin inoverdosage.
AcidificationwithAmmoniumchloridecanpromoteexcretionof
weakbasicdrugsi.e phenobarbitone inoverdosage.
2. IonTrapping(pHpartition): It meansthatweakacidstendto
accumulateinthecompartmentsofrelativelyhighpHwhereas
weakbasisdothereverse.
SodrugscanbetrappedduetopHdifferencein:
Stomach,intestinalcontents
breastmilk,prostatic/vaginalsecretions.
IncreasingplasmapHcausesweaklyacidicdrugstobe
extractedfromtheC.N.Sintoplasma.
 AqueousDiffusion
(Intracellular/Paracellulardiffusion/ filtration)
Passivediffusion
Throughtheaqueouspores
Alongaconcentrationgradient
Smallwatersolubledrugmoleculesinsolutionform(M.W
upto20,000 30,000)
Ifthedrugischarged,itsfluxisalsoinfluencedbyelectrical
fields(e.g.themembranepotential,transtubularpotential)
 Importance
Themostimportantmechanismbywhichdrugspass
throughcapillaryendotheliummembrane.
Importantinglomerularfiltration.
Proteinbounddrugmoleculescannotpass.
Brainandtestesareprotectedfrommanycirculatingdrugs.
 CarrierMediatedTransport
Importantfordrugmoleculestoolargeortooinsoluble
inlipidtodiffusepassivelythroughmembranes.
Carriersaretransmembraneproteins.Thedrug
moleculeschemicallyrelatedtonaturallyoccurring
peptides,aminoacids,orsugarscanusethesecarriers.
Carrierbindsoneormoremoleculesorions,changes
conformation&releasesthemontheothersiteof
membrane.
Mainsites:
Renaltubule.
Biliarytract.
Bloodbrainbarrier.(BBB)
Gastrointestinaltract.(GIT)
Types:
ActiveTransport
FacilitatedDiffusion:
Activetransport:Thecharacteristicsare:
1. Againsttheconcentrationgradient
2. Energydependent,obtainedfromhydrolysisofATP
3. Carrierisrequired
4. Selective
5. Saturable
6. Competitiveinhibitionbyanotherdrugbindingtosamecarrier.
Examples:
1. TransportofLEVODOPAintothebrain.
2. Activeabsorptionof5FLUOROURACILthroughtheGutwall.
3. ActiveproximalrenaltubularsecretionofPENICILLIN&
PROBENECID.
SoexcretionofPENICILLINcanbeinhibitedbyPROBENECID.
4.Somedrugscanblocknaturalcarriersi.e.COCAINEcanblock
catecholamineuptakeatadrenergicnerveendings.
Reversetransporters: Carriersspecializedinexpellingforeign
moleculesastheenterthecells.
OnelargefamilyisABC(ATPbindingcassette)family&
includes.
1. Pglycoproteinormultidrugresistancetype1(MDR1)
transporter,foundinthebrain,testes&othertissuesand
insomedrugresistantneoplastic cells
Itcanbeinhibitedbygrapefruitjuice&certaindrugsi.e
VERAPAMIL.
2. Multidrugresistanceassociatedprotein(MRP)
transportersplayimportantroleinexcretionofdrugorits
metabolitesintourineorbile.
FacilitatedDiffusion:Amechanismtoenhancediffusion
ofdrugs withlowlipidsolubility.
Alongaconcentrationgradient
Carriermediated:
Carrierincreaseslipidsolubilityofdrugrateof
diffusion
Notenergydependent
Saturable
Competitiveinhibition
e.g.GlucoseentryintothecellbyGlucosetransportersGLUT1
GLUT5
 Pinocytosis(Endocytosis&Exocytosis)

Specificreceptors fortransportproteinsmustbepresentforthis
processtowork.
Endocytosis: Drugswhichhaveverylargemolecules
(macromolecules)canbeengulfedbythecellmembraneina
vesicle&carriedintothecell&releasedwithinthecellby
pinchingoffthevesicle&breakdownofitsmembrane.
Examples:
TransportofvitaminB12withabindingprotein(intrinsic
factor)acrossgutwall.
IronistransportedintohemoglobinsynthesizingRBCs
precursorswithtransferrin.
Exocytosis:
Exocytosis istheeverse ofendocytosis.It is
responsibleforsecretionofmanysubstancesfrom
cells.
e.g.Expulsionofneurotransmittersintothesynaptic
cleft.
Theneurotransmittersubstancesarestoredin
membraneboundvesiclesinnerveendingsto
protectthemfrommetabolicdestruction.
Appropriateactivationofnerveendingcauses
expulsionofitscontentsintothesynapticcleft.