GIT Absorption of Drugs Biopharmaceutics NIPER

Mechanisms of Drug Absorption through GIT
Factors Affecting Drug Absorption
Assessment of GI Drug Absorption
- PAMPA method
-CaCO Method
-Inverted intestinal Sac method and many more methods

1. 2. GIT Absorption of Drugs
BRIJESH YADAV
MS(Pharm) Pharmcology and Toxicology
NIPER Hajipur

2. INTRODUCTION
⚫Adruginjectedintravascularly(intravenouslyand/orintra-
arterially)directlyentersthesystemiccirculationandexertsits
pharmacologicaleffects.
⚫Ifintendedtoactsystemically,suchdrugscanexerttheir
pharmacologicalactionsonlywhentheycomeintoblood
circulationfromtheirsiteofapplication, forthis,
absorptionisanimportantprerequisitestep.
⚫Drugabsorptionisdefinedastheprocessofmovementof
unchangeddrugfromthesiteofadministrationtosystemic
circulation
⚫Following absorption, the effectiveness of a drug can only be
assessed by its concentration at the site of action.

3. ⚫Therealwaysexistacorrelationbetweentheplasma concentration
ofadrugandthetherapeuticresponse
⚫Absorptioncanalsobedefinedastheprocessofmovement
ofunchangeddrugfromthesiteofadministrationtothesite
ofmeasurementi.e.plasma.
⚫This definition takes into account the loss of drug that occurs
after oral administration due topre-systemic metabolism or
first-pass effect.

4. ⚫Adrugthatiscompletelybutslowlyabsorbed mayfail to
showtherapeuticresponseastheplasma concentration
fordesiredeffectisneverachieved.
⚫Onthecontrary,arapidlyabsorbeddrugattainsthe
therapeuticleveleasilytoelicitpharmacologicaleffect.
⚫Thus,boththerateandtheextentofdrugabsorption
areimportant.
⚫SUCH ABSORPTION PATTERN HAS SEVERAL
ADVANTAGES:
⚫Lessersusceptibilityofthedrugfordegradationor
interactionduetorapidabsorption.
⚫Higherbloodlevelsandrapidonsetofaction.
⚫Moreuniform,greaterandreproducibletherapeutic
response.

5. Drugsthathavetoenterthesystemiccirculationtoexert
their effectcanbeadministeredbythreemajorroutes:
⚫TheEnteralRoute:includesperorali.e.gastrointestinal,sublingual/buccaland
rectalroutes.TheGI routeisthemostcommonforadministrationofmajorityof
drugs.
⚫TheParenteralRoute:includesallroutesofadministrationthroughorunder
oneormorelayersofskin.Whilenoabsorptionisrequiredwhenthedrugis
administeredi.v.,itisnecessaryforextravascularparenteralrouteslikethe
subcutaneousandtheintramuscularroutes.
⚫TheTopicalRoute:includesskin,eyesorotherspecificmembranes.The
intranasal,inhalation,intravaginalandtransdermalroutesmaybeconsidered
enteralortopicalaccordingtodifferentdefinitions.

6. BIOAVAILABILITY/ABSORPTIONOFDRUGFROMCOMMON
ROUTESOFDRUGADMINISTRATION
ROUTE
BIOAVAILABILIT
Y ADVANTAGES DISADVANTAGES
Intravenous(IV) ·Complete
(100%)
systemicdrug
absorption.
·Drugisgivenfor
immediateor
controlledeffect.
·Increasedchanceforadversereaction.
·Mayinjectlargefluid
volumes.
·Possibleanaphylaxis.
·Suitablefor irritating
drugs
·Requiresskillininsertionofinfusionset.
·Tissuedamageat siteofinjection(infiltration,
necrosis,orsterileabscess).
Intramuscular
injection(IM)
·Rapid
absorption
fromaqueous
solutions.
·Easiertoinjectthan
intravenous
injection.
·Irritatingdrugsmaybeverypainful.
·Slowabsorption
fromnon-aqueous
(oily)solutions.
·Largervolumesmay
beusedcompared
tosubcutaneous
solution.
·Variableratesofabsorptiondependingupon
musclegroupinjectedandbloodflow.
Subcutaneous
injection(SC)
·Rapid
absorption
fromaqueous
solution.
·Generally,usedfor
vaccinesanddrugs
notabsorbedorally
e.g.insulin.
·Rateofdrugabsorptiondependsuponblood
flowandinjectionvolume.
·Slow
absorption
fromdepot
formulations.
PARENTERALROUTE

7. ROUTE
BIOAVAILABILI
TY ADVANTAGES DISADVANTAGES
Buccalor
sublingual(SL)
·Rapidabsorption
oflipid-soluble
drugs.
Nopresystemicmetabolism.
·Somedrugmaybeswallowed.Not
formostdrugsordrugswithhighdoses.
Oral(PO) ·Absorptionmay
vary.Generally
slowerabsorption
ratecomparedtoIV
bolusorIMinjection.
·Safestandeasiestrouteofdrug
administration.
·SomedrugsareunstableinGIT,or
undergopresystemicmetabolismor
show erraticabsorption.
·Suitableforbothimmediate-release
andmodified-releasedrugproducts.
Rectal(PR) ·Absorptionmay
varyfrom
suppository.
·Usefulwhenpatientcannot
swallowmedication.
·Absorptionmaybeerratic.
Suppositorymaymigratetodifferent
position.
·Morereliable
absorptionfrom
enema(solution).
·Usedforlocalandsystemiceffects.·Somepatientdiscomfort.
ENTERALROUTE

8. ROUTE BIOAVAILABILITY ADVANTAGES DISADVANTAGES
Transdermal ·Slowabsorption,rate
mayvary.
·Transdermaldelivery
system(patch)iseasy
touseandwithdraw.
·Someirritationbypatchordrug.
·Increasedabsorption
withocclusive
dressings.
·Continuousreleasefora
specifiedperiod.
·Permeabilityofskinvariablewith
condition,anatomicsite,age,and
gender.
·Usedforlipid-soluble
drugswithlowdose
andlowMW.
·Typeofcreamorointmentbase
affectsdrugreleaseandabsorption.
·Lowpresystemic
metabolism.
Inhalation ·Rapidabsorption. ·Maybeusedforlocalor
systemiceffects.
·Particlesizeofdrugdetermines
anatomicplacementinrespiratory
tract.
OTHERROUTES

9. GASTROINTESTINAL
ABSORPTIONOFDRUGS

10. CELLMEMBRANE:STRUCTUREANDPHYSIOLOGY
⚫Foradrugtobeabsorbedanddistributedintoorgans
andtissuesandeliminatedfromthebody,itmustpass
throughoneormorebiologicalmembranes/barriersat
variouslocations.
⚫Suchamovementofdrug acrossthemembrane iscalledas
Drugtransport.

11. BASICSTRUCTUREOFCELLMEMBRANE

12. MECHANISMSOFDRUGABSORPTION
⚫Thethreebroadcategoriesofdrugtransport
mechanismsinvolvedinabsorptionare–
⚫Transcellular/intracellulartransport
⚫Paracellular/intercellulartransport
⚫Vesiculartransport

13. TRANSCELLULAR /INTRACELLULAR TRANSPORT
⚫Transcellular/IntracellularTransport–isdefinedasthepassageofdrugs
acrossthe GIepithelium.Itisthemostcommonpathwayfordrug
transport.
⚫The3stepsinvolvedintranscellulartransportofdrugsare–
1.PermeationofGIepithelialcellmembrane,alipoidalbarrier–thisis
themajorobstacletodrugabsorption.
2.Movementacrosstheintracellularspace(cytosol).
3.Permeationofthelateralorbasolateralmembrane-thisisof
1.secondaryimportance.

14. VARIOUSTRANSCELLULAR TRANSPORTPROCESSES
PassiveTransportProcesses–
✓
✓ Thesetransportprocessesdonotrequireenergyotherthanthatofmolecular
motion(Brownianmotion)topassthroughthelipidbilayer.
Passivetransportprocessescanbefurtherclassifiedintofollowingtypes–
⚫Passivediffusion.
⚫Poretransport.
⚫Ion-pairtransport.
⚫Facilitated-ormediated-diffusion.
ActiveTransportProcesses–
✓ThistransportprocessrequiresenergyfromATPtomovedrugmoleculesfrom
extracellulartointracellularmilieu.
✓Theseareoftwotypes–
⚫Primaryactivetransport.
⚫Secondaryactivetransport–thisprocessisfurthersubdivided
intotwo–
Symport(co-transport).
Antiport(counter-transport).

15. ❑Paracellular/IntercellularTransport–isdefinedasthetransport of
drugsthroughthejunctionsbetweentheGIepithelialcells.
❑Thetwoparacellulartransportmechanismsinvolvedindrug
absorptionare–
1. Permeationthroughtightjunctionsofepithelialcells
⚫thisprocessbasicallyoccursthroughopeningswhicharelittle
biggerthantheaqueouspores.
⚫Compoundssuchasinsulinandcardiacglycosidesaretakenup
thismechanism.
2. Persorption
⚫ispermeationofdrugthroughtemporaryopeningsformedby
sheddingoftwoneighbouringepithelialcellsintothelumen.
PARACELLULAR/INTERCELLULAR
TRANSPORT

16. Paracellulartransportdiffersfromporetransport
•Paracellulartransportinvolvestransferofdrugacross
epitheliumandthroughthecellularjunctions.
•Incaseofporetransport,themoleculesaretransferred from
outsideoftheepithelialcellintothecellthroughpores
presentinthecellmembrane.

17. VesicularorCorpuscularTransport (Endocytosis)
❑Likeactivetransport,thesearealsoenergydependentprocessesbut
involvetransportof substanceswithinvesiclesintoacell.
❑Sincethemechanisminvolvestransportacrossthecellmembrane,the
processcanalsobeclassifiedastranscellular.
❑Vesiculartransportofdrugscanbeclassedintotwocategories
Pinocytosis.
Phagocytosis.
VESICULARORCORPUSCULAR TRANSPORT

18. ILLUSTRATIVECOMPARISONOF
TRANSCELLULAR,PARACELLULARAND
VESICULAR
TRANSPORTMECHANISMS

19. PASSIVEDIFFUSION
▪Alsocallednon-ionicdiffusion
▪Itisthemajorprocessforabsorptionofmorethan90%ofthedrugs.
▪Thedrivingforceforthisprocessistheconcentrationor
electrochemicalgradient.
▪Itisdefinedasthedifferenceinthedrugconcentrationoneithersideofthe
membrane.Drugmovementisaresultofthekineticenergyof
molecules.
▪Sincenoenergysourceisrequired,theprocessiscalledaspassive
diffusion.
•During passive diffusion, the drug present in the aqueous
solution at the absorption site partitions and dissolves in the
lipid material of the membrane and finally leaves it by
dissolving again in an aqueous medium, this time at the inside of
the membrane.

20. ⚫PassivediffusionisbestexpressedbyFICK’SFIRSTLAWOF DIFFUSION,
⚫Thedrugmoleculesdiffusefromaregionofhigher
concentrationtooneoflowerconcentrationuntil
equilibriumisattainedandthattherateofdiffusionisdirectly
proportionaltotheconcentrationgradientacrossthemembrane.

21. CHARACTERISTICSOFPASSIVEDIFFUSION
1.Thedrugmovesdowntheconcentrationgradientindicatingdownhill
transport.
2.Theprocessisenergy-independentandnon-saturable.
3.Therateofdrugtransferisdirectlyproportionaltotheconcentration
gradientbetweenGIfluidsandthebloodcompartment.
4.Greatertheareaandlesserthethicknessofthemembrane,fasterthe
diffusion;thus,morerapidistherateofdrugabsorptionfromthe
intestinethanfromthestomach.
5.Theprocessisrapidovershortdistancesandsloweroverlong
distances.
6. Equilibrium is attained when the concentration on either side of
the membrane becomes equal.
7.Drugs which can exist in both ionised and unionised forms approach
equilibrium primarily by the transfer of the unionised species; the rate of
transfer of unionised species is 3 to 4 times the rate for ionised drugs.
8. Greater the membrane/water partition coefficient of drug, faster the
absorption; since the membrane is lipoidal in nature, a lipophilic drug
diffuses at a faster rate by solubilising in the lipid layer of the membrane.

22. ❑ThedrugdiffusesrapidlywhenthevolumeofGIfluidislow;
conversely,dilutionofGIfluidsdecreasesthedrugconcentrationin
thesefluids(C
GIT)andlowertheconcentrationgradient(C
GIT–C).
Thisphenomenonis,however,madeuseofintreating
casesoforaloverdoseorpoisoning.
❑Theprocessisdependent,toalesserextent,onthesquarerootof
themolecularsizeofthedrug–
Drugshavingmolecularweightsbetween100to400
Daltonsareeffectivelyabsorbedpassively.
❑Thediffusiongenerallydecreaseswithincreaseinthemolecular
weightofthecompound.
Exceptions—forexample,cyclosporineA, apeptideof
molecularweight1200,isabsorbedorallymuchbetterthanany
otherpeptide.

23. ❑Initially,whenthedrugisingested,CGIT>>Candalarge
concentrationgradientexiststherebyactingasthedrivingforce
forabsorption.
❑Asequilibriumapproaches,thedrugdiffusionshouldstopand
consequentlyalargefractionofdrugmayremainunabsorbed.
❑Butthisisnotthecase;oncethepassivelyabsorbeddrugenters
blood,itisrapidlysweptawayanddistributedintoamuch
largervolume ofbodyfluids
hence,theconcentrationofdrugattheabsorption
site,CGIT,ismaintainedgreaterthantheconcentrationofdrug
inplasma.
❑Suchaconditioniscalledassinkconditionfordrugabsorption.

24. ❑Asaresult,equationmaybesimplifiedto
❑Itisanexpressionforafirst-orderprocess.
❑Thus,passivediffusionfollowsfirst-orderkinetics.
❑Sincealargeconcentrationgradientalwaysexistsattheabsorptionsite
forpassivediffusion,therateofdrugabsorptionisusuallymorerapid
thantherateofelimination.
❑Besides,dilutionanddistributionof theabsorbeddrugintoalargepool
ofbodyfluidsanditssubsequentbindingtovarioustissuesareother
reasonsforeliminationbeingslowerthanabsorption.
G I T
PC
dQ
=
dt

25. RELATIVEPASSIVEDIFFUSIONRATEOF
DIFFERENTTYPESOFMOLECULES
ILLUSTRATIONOFTHERELATIVEPERMEABILITYOFDIFFERENTMOLECULESTOLIPIDBILAYER.

26. PORETRANSPORT
❑Itisalsocalledasconvectivetransport,bulkflowor
filtration.
❑Thismechanismisresponsiblefortransportofmolecules
intothecellthroughtheproteinchannelspresentinthe
cellmembrane.

27. ❑Thedrivingforceisconstitutedbythehydrostaticpressureorthe
osmoticdifferencesacrossthemembraneduetowhichbulkflowof
wateralongwithsmallsolidmoleculesoccursthroughsuchaqueous
channels.
Waterfluxthatpromotessuchatransportiscalledassolvent
drag.
❑Theprocessisimportantintheabsorptionoflowmolecularweight
(lessthan100),lowmolecularsize(smallerthanthediameterofthe
pore)andgenerallywater-solubledrugsthroughnarrow,aqueous-
filledchannelsorporesinthemembranestructure—forexample,
urea,waterandsugars.
CHARACTERISTICSOFPORETRANSPORT

28. ❑Chain-likeorlinearcompoundsofmolecularweightup
to400Daltonscanbeabsorbedbyfiltration.
❑Drugpermeationthroughwater-filledchannelsisof
particularimportanceinrenalexcretion,removalofdrug
fromthecerebrospinalfluidandentryofdrugsintothe
liver.

29. ION-PAIRTRANSPORT
❑Mechanismthatexplainstheabsorptionofdrugslikequaternary
ammoniumcompoundsandsulphonicacids,whichioniseunderall
pHconditions,ision-pairtransport.
❑DespitetheirlowO/Wpartitioncoefficientvalues,suchagents
penetratethemembranebyformingreversibleneutralcomplexes
withendogenousionsoftheGITlikemucin.
❑Suchneutralcomplexeshaveboththerequiredlipophilicityaswell
asaqueoussolubilityforpassivediffusion.
❑SuchaphenomenoniscalledasION-PAIRTRANSPORT.
Propranolol,abasicdrugthatformsanionpairwith
oleicacid,isabsorbedbythismechanism.

30. ION-PAIRTRANSPORTOFACATIONICDRUG

31. ⚫Somepolardrugscrossthemembranemorereadilythancan
bepredictedfromtheirconcentrationgradientandpartition
coefficientvalues.
⚫Thissuggests presenceofspecializedtransportmechanisms
withoutwhichmanyessentialwater-solublenutrientslike
monosaccharides,aminoacidsandvitaminswillbepoorly
absorbed.
⚫Themechanismisthoughttoinvolveacomponentofthe
membranecalledasthecarrierthat bindsreversiblyornon-
covalentlywiththesolutemoleculestobetransported.
CARRIERMEDIATEDTRANSPORT

32. ⚫Thiscarrier-solutecomplextraverses acrossthemembraneto
theothersidewhereit dissociatesanddischargesthe solute
molecule.
⚫Thecarrierthenreturnstoitsoriginalsitetocompletethe
cyclebyacceptingafreshmoleculeofsolute.
⚫Carriersinmembranes areproteins(transportproteins)and
maybeanenzymeorsomeothercomponentofthe
membrane.
⚫Theyarenumerousinallbiologicalmembranesandare
founddissolvedinthelipidbilayerofthemembrane.

33. IMPORTANTCHARACTERISTICSOF
CARRIER-MEDIATEDTRANSPORT
⚫Acarrierproteinalwayshasanuncharged(non-polar)outer
surfacewhichallowsittobesolublewithinthelipid ofthe
membrane.
⚫Thecarriershavenodirectionality;theyworkwithsame
efficiencyinbothdirections.
⚫Thetransportprocessisstructure-specifici.e.thecarriershave
specialaffinityforandtransferadrugofspecificchemical
structureonly(i.e.lockandkeyarrangement);generallythe
carriershavespecialaffinityforessentialnutrients.

34. ⚫Sincethesystemisstructure-specific,drugshavingstructure
similartoessentialnutrients,calledasfalsenutrients,are
absorbedbythesamecarriersystem.
Thismechanismisofparticularimportanceinthe
absorptionofseveralantineoplasticagentslike 5-fluorouracil
and5-bromouracilwhichserveasfalsenutrients.
⚫Asthenumberofcarriersislimited,thetransportsystemis
subjecttocompetitionbetween agentshavingsimilar
structure.

35. ⚫Sincethenumberofcarriersis
limited, thesystemiscapacity-
limited i.e.at higherdrug
concentration;thesystembecomes
saturatedandapproachesan
asymptote
⚫Suchacapacity-limitedprocesscan
beadequatelydescribedbymixed
orderkinetics,alsocalledas
Michaelis-Menten,saturationor
non-linearkinetics

36. ⚫Specializedabsorption orcarrier-mediated absorptiongenerally
occursfromspecificsitesoftheintestinaltractwhicharerich
innumberofcarriers.
Suchanareainwhichthecarriersystemismostdense
iscalled asabsorptionwindow.Drugsabsorbedthroughsuch
absorptionwindowsare poorcandidatesforcontrolled release
formulations.
⚫Twotypesofcarrier-mediatedtransportsystemsinclude
⚫Facilitateddiffusionand
⚫Activetransport.

37. FACILITATEDDIFFUSION
⚫Itisa carrier-mediatedtransportsystem thatoperatesdownthe
concentrationgradient(downhilltransport)butatamuchafaster
ratethancanbeaccountedbysimplepassivediffusion.
⚫Thedrivingforceisconcentrationgradient(henceapassive
process).Sincenoenergyexpenditureisinvolved, theprocessis
notinhibited
⚫Facilitateddiffusionisoflimitedimportanceintheabsorptionof
drugs.

38. ⚫Examplesofsuchatransportsystemincludeentryofglucose
intoRBCsandintestinalabsorptionofvitaminsB1andB2.
⚫AclassicexampleofpassivefacilitateddiffusionistheGI
absorptionofvitaminB12.
⚫Anintrinsicfactor(IF),aglycoproteinproducedbythe
gastricparietalcells,formsacomplexwithvitaminB12
whichisthentransportedacrosstheintestinalmembraneby
acarriersystem

39. FACILITATEDDIFFUSIONOFVITAMINB12

40. ACTIVETRANSPORT
⚫ThistransportmechanismrequiresenergyintheformATP.
Activetransportmechanismsarefurthersubdividedinto–
⚫Primaryactivetransport
⚫Secondaryactivetransport

41. Primaryactivetransport
⚫Inthisprocess,there isdirectATP requirement.Moreover,
theprocesstransfersonlyoneionormoleculeandinonly
onedirection,andhencecalledasuniportere.g.absorption
ofglucose. Carrierproteinsinvolved inprimaryactive
transportareoftwotypes–
⚫Iontransporters
⚫ABC(ATP-bindingcassette)transporters

42. IONTRANSPORTERS
⚫Responsiblefortransportingionsinoroutofcells.
⚫AclassicexampleofATP-drivenionpumpisprotonpump
whichisimplicatedinacidificationofintracellular
compartments.
⚫Twotypesofiontransporterswhichplayimportantrolein
theintestinalabsorptionofdrugshavebeen identified–
⚫Organicaniontransporter –whichaidsabsorptionofdrugssuch
aspravastatinandatorvastatin.
⚫Organiccationtransporter–whichaidsabsorptionofdrugssuch
asdiphenhydramine.

43. ABC(ATP-bindingcassette)transporters
⚫Responsiblefortransportingsmallforeignmolecules (like
drugsandtoxins)especiallyoutofcells(andthuscalledas
effluxpumps)whichmakethemclinicallyimportant.
⚫AclassicexampleofABCtransporterisP-glycoprotein
(P-gp).

44. Activeabsorptionofadrug

45. Activetransport isamoreimportant processthanfacilitated
diffusioninthe absorptionofnutrientsanddrugsanddiffers
fromitinseveralrespects:
⚫Thedrugistransportedfromaregionoflowertooneofhigher
concentrationi.e.againsttheconcentrationgradient(inthecaseof
ions,againstanelectrochemicalgradient)oruphilltransport,without
anyregardforequilibrium.
⚫Theprocess isfaster thanpassivediffusion.
⚫Sincetheprocessisuphill,energyisrequired intheworkdonebythe
carrier.
⚫Asthe processrequiresexpenditureofenergy,itcanbeinhibitedby
metabolicpoisons thatinterferewithenergyproductionlike
fluorides,cyanideanddinitrophenolandlackofoxygen,etc.

46. ⚫Endogenous substances thataretransportedactivelyincludesodium,
potassium,calcium,iron,glucose,certainaminoacidsandvitaminslike
niacin,pyridoxinandascorbicacid.
⚫Drugshavingstructuralsimilaritytosuchagentsareabsorbedactively,
particularlytheagentsusefulincancerchemotherapy.
⚫Examplesincludeabsorptionof5-fluorouraciland5-bromouracilviathe
pyrimidinetransportsystem,absorptionofmethyldopaand levodopavia
anL-aminoacidtransportsystemandabsorptionofACEinhibitor
enalaprilviathesmallpeptidecarriersystem.
⚫Agoodexampleofcompetitiveinhibitionofdrugabsorptionviaactive
transportistheimpairedabsorptionoflevodopawheningested with
mealsrichinproteins.
⚫Activetransportisalsoimportantinrenalandbiliaryexcretionofmany
drugsandtheirmetabolitesandsecretionofcertainacidsoutoftheCNS.

47. COMPARISONBETWEENACTIVEANDPASSIVETRANSPORT

48. ENDOCYTOSIS
⚫Itisaminortransportmechanismwhichinvolves
engulfingextracellularmaterialswithinasegmentofthe
cellmembranetoformasacculeor avesicle(hencealso
calledascorpuscularorvesiculartransport)whichisthen
pinched-offintracellularly
⚫Thisistheonlytransportmechanismwherebyadrugor
compounddoesnothavetobeinanaqueoussolutionin
ordertobeabsorbed.

49. ENDOCYTICUPTAKEOFMACROMOLECULES

50. ⚫Thisphenomenonisresponsibleforthecellularuptake
ofmacromolecularnutrientslikefatsandstarch,oil
solublevitaminslikeA,D,EandK,watersolublevitamin
likeB12anddrugssuchasinsulin.
⚫Anothersignificanceofsuchaprocessisthatthedrugis
absorbedintothelymphaticcirculationthereby
bypassingfirst-passhepaticmetabolism.

51. ⚫Endocytosisincludestwotypesofprocesses:
⚫Phagocytosis(celleating):adsorptiveuptakeofsolidparticulates,
and
⚫Pinocytosis(celldrinking):uptakeoffluidsolute.
⚫OrallyadministeredSabinpoliovaccine,largeproteinmoleculesand
thebotulismtoxin(thatcausesfood poisoning)arethoughttobe
absorbedbypinocytosis.
⚫Sometimes,anendocyticvesicleistransferredfromoneextracellular
compartmenttoanother.Suchaphenomenoniscalledastranscytosis.

53. Factors Affecting drug absorption through GIT
A.PHARMACEUTIC FACTORS : include factors relating to the physicochemical
properties of the drug, and dosage form characteristics and pharmaceutic ingredients
I.Physicochemical Properties of Drug Substances

74. ❖FACTORSAFFECTINGDRUGABSORPTION
A.Physicochemicalfactors:
1)Drugsolubility&dissolutionrate (STUDY
theories of dissolution from pearson than make
notes of it )
2)Particlesize& effectivesurfacearea
3)Polymorphism&amorphism
4)Pseudoploymorphism(hydrates/solvates)
5)Saltformofthedrug
6)Lipophilicityofthedrug
7)pKaofdrug&gastrointestinalpH
pH-Partition
hypothesis
8)Drugstability
9) Complexation & Chelation

75. B.Pharmaceutical (Formulation and dosage form) factors:
1)Disintegrationtime(tablets/capsules)
2)Dissolutiontime
3)Manufacturingvariables
4)Pharmaceuticalingredients(excipients/adjuvants)
5)Nature&typeofdosageform
6)Productage&storagecondition
C.Biological (Physiological) Factors:
1)Routeofadministration
2)Membranephysiology
a)Natureofcellmembrane
b)Transportprocesses
3)Age
4)Gastricemptyingtime
5)Intestinaltransittime

76. 6)GastrointestinalpH
7)Diseasestates
8)Bloodflow throughtheGIT
9)Gastrointestinalcontents:
a)Food-druginteractions
b)Fluids
c)OthernormalGIcontents
10)Presystemicmetabolismby:
a)Luminalenzymes
b)Gutwallenzymes
c)Bacterialenzymes
d)Hepaticenzymes

77. PHYSICOCHEMICALFACTORS
1)Drugsolubility&dissolutionrate:
Theratedeterminingstepsinabsorptionoforallyadministered
drugsare:
1.Rateofdissolution
2.Rateofdrugpermeationthroughthebio-membrane.
➢Dissolutionisratedeterminingstepforhydrophobic&poorly
aqueoussolubledrugs.
E.g.Griesiofulvin&Spironolactone.
➢Permeationistheratedeterminingstepforhydrophilic&high
aqueoussolubledrugs.
E.g.cromolynsodiumorNeomycin.
➢Prerequisitefortheabsorptionofadrugisthatitmustbepresent
inaqueoussolution&thisisdependsondrug’saqueoussolubility
&itsdissolutionrate.

79. 2)Particlesizeandeffectivesurfacearea:
➢Particlesizemayplayamajor roleindrugabsorption.
➢Dissolutionrateofsolidparticlesisproportionalto
surfacearea.
➢Smallerparticlesize,greatersurfaceareathenhigher
willbedissolutionrate,becausedissolutionisthoughtto
takeplaceatthesurfaceareaofthesolute(Drug).
➢Particlesizereductionhasbeenusedtoincreasethe
absorptionofalargenumberofpoorlysolubledrugs.
➢E.g.Bishydroxycoumarin,digoxin,griseofulvin
➢Twotypesofsurfacearea
1)Absolutesurfacearea
2)Effectivesurfacearea
09

80. ➢Inabsorptionstudiestheeffectivesurfaceareaisof
muchimportantthanabsolute.
➢Toincreasetheeffectivesurfacearea,wehaveto
reducethesizeofparticlesupto0.1micron.Sothesecan
beachievedby“micronisationprocess’’.
➢Butinthesecaseonemostimportantthingtobekeepin
mindthatwhichtypeofdrugismicronisedifitis:
a)HYDROPHILICORb)HYDROPHOBIC
a)HYDROPHILICDRUGS:
➢Inhydrophilicdrugsthesmallparticleshavehigher
energythanthebulkofthesolidresultinginanincreased
interactionwiththesolvent.
10

81. ▪Examples,
1.Griesiofulvin
micronisation.
–Dosereducedtohalfdueto
2.Spironolactone–thedosewasdecreasedto20times.
3.Digoxin–thebioavailabilitywasfoundtobe100%in
micronizedtablets.
➢Aftermicronisationitwasfoundthattheabsorption
efficiencywashighlyincreased
b)HYDROPHOBIC DRUGS:
➢Inthismicronisationtechniquiesresultsindecreased
effectivesurfacearea&thusfallindissolutionrate.
REASONs:
1)Thehydrophobicsurfaceofthedrugsadsorbsaironto
theirsurfacewhichinhibitstheirwettability.
11

82. 2)Theparticlesreaggregatestoformlargeparticlesdueto
theirhighsurfacefreeenergy,whicheitherfloatonthe
surfaceorsettleonthebottomofthedissolutionmedium.
3)Electricallyinducedagglomerationowingtosurface
chargespreventsintimatecontactofthedrugwiththe
dissolutionmedium.
➢Suchhydrophobicdrugscanbeconvertedtotheir
effectivesurfacearea.
a)Useof surfactantasawettingagentwhich
-decreasetheinterfacialtention.
-displacetheabsorbedairwiththesolvent.Eg.phenacetin
b)AddhydrophilicdiluentslikePEG,PVP,dextroseetc.
whichcoatthesurfaceof hydrophobicdrugparticles.

83. 3)Polymorphism&Amorphism:
➢Dependingupontheinternalstructure,asolidcanexisteitherina
crystallineoramorphousform.Whenasubstanceexistsinmore
thanonecrystallineform,thedifferentformsaredesignatedas
polymorphs,andthephenomenonaspolymorphism.
➢Polymorpsareoftwotypes:
1)Enantiotropicpolymorphistheonewhichcanbereversibly
changedintoanthorformbyalteringthetemperatureor
pressure.E.g.Sulfur.
2)Monotropicpolymorphistheonewhichisunstableatallthe
temperatureorpressures.E.g.glycerylstrarates.
➢Thepolymorphsdifferfromeachotherwithrespecttotheir
physicalpropertiessuchassolubility,meltingpoint,density,
hardnessandcompressioncharacteristics.Thus,thesechangein
physicalpropertiesaffectthedissolutionpropertiesandhencethe
absorption.

84. ➢E.g.Thevitaminriboflavinexistsinseveralpolymorphicforms,
polymorphicformIIIofriboflavinis20timesmorewatersoluble
thantheformI.
➢AMORPHISM:Somedrugscanexistinamorphousform(i.e.
havingnointernalcrystalstructure).Suchdrugrepresentsthe
highestenergystate.
➢Theyhavegreateraqueoussolubilitythanthecrystallineforms
becauseaenergyrequiredtotransferamoleculefromthecrystal
latticeisgreaterthanthatrequiredfornon-crystalline(amorphous
form).
➢Forexample:theamorphousformofNovobiocinis10times
moresolublethanthecrystallineform.Thus,theorderofdifferent
soliddosageformsofthedrugsis
Amorphous>Meta-stable>stable

85. 4)Pseudoploymorphism:Whenthesolventmoleculesare
entrappedinthecrystallinestructureofthepolymorph,itis
knownaspseudo-polymorphism.
➢Solvates:thestoichiometrictypeofadductswherethe
solventmoleculesareincorporatedinthecrystallatticeofthe
solidarecalledasthesolvates,andthetrappedsolventas
solventofcrystallization.
➢Hydrates:whenthesolventinassociationwiththedrugis
water,thesolvateisknownasahydrate.
➢Hydrates/Solvatesarepseudo-polymorphswherehydratesare
lesssolubleandsolvatesaremoresolubleandthusaffectthe
absorptionaccordingly.
➢Forexample:n-pentanolsolvatesoffludrocortisoneand
succinyl-sulfathiazolehavegreateraqueoussolubilitythanthe
non-solvates.

86. (5)Saltformofdrug:
➢Whileconsideringthesaltformofdrug,pHofthediffusion
layerisimportantnotthepHofthebulkofthesolution.
➢Exampleofsaltofweakacid.-ItincreasesthepHofthe
diffusionlayer,whichpromotesthesolubilityanddissolution
ofaweakacidandabsorptionisboundtoberapid.
➢Otherapproachtoenhancethedissolutionandabsorption
rateofcertaindrugsistheformationofin–situsaltformation

87. i.e.increasinginpHofmicroenvironment ofdrugby
incorporationofabufferingagent.E.g.aspirin,penicillin
➢Butsometimesmoresolublesaltformofdrugmayresultinpoorabsorption.
e.g.sodiumsaltofphenobarbitoneviz.,itstabletswellsanddidnotget
disintegrate,thusdissolvedslowlyandresultsinpoorabsorption.

88. 6&7)pH-Partionhypothesis:
➢Thetheorystatesthatfordrugcompoundsofmolecular
weightmorethan100,whichareprimarilytransported
acrossthebio-membranebypassivediffusion,theprocess
ofabsorptionisgovernedby:
1.ThedissociationconstantpKaofthedrug.
2.Thelipidsolubilityoftheun-ionizeddrug.
3.ThepHattheabsorptionsite.

89. A)DRUGpKaANDGIpH:
➢Amountofdrugthatexistsinun-ionizedformandinionizedform
isafunctionofpKaofdrugandpHofthefluidattheabsorption
site,anditcanbedeterminedbyHanderson-Hasselbachequation:
•Forweakacids,
pH=pKa+log[ionized]
[un-ionized] ..(1.1)
%Drugionized=10
pH-pKax 100 …(1.2)
1+10
pH-pKa
•Forweakbases, pH=pKa+log[un-ionized]
[ionized]…(1.3)
%Drugionized=10
pKa-pHx100
1+10
pKa-pH
…(1.4)

90. ➢Ifthereisamembranebarrierthatseparatesthe
aqueoussolutionsofdifferentpHsuchastheGITandthe
plasma,thenthetheoreticalratioRofdrugconcentration
oneithersideofthemembranecanbegivenbythe
followingequations:
•Forweakacids,
Ra=C
GIT
C
plasma
= 1+10
pHGIT-pKa
1+10
pHplasma-pKa
….(1.5)
•Forweakbases,
Rb=C
GIT
C
plasma
= 1+10
pKa-pHGIT
1+10
pKa-pHplasma....(1.6)

92. B)LIPOPHILICITYANDDRUGABSORPTION:
➢Thelipidsolubilityofthedrugisdeterminedformits
oil/waterpartitionco-efficient(Ko/w)value,whereby
theincreaseinthisvalueindicatestheincreasein
percentagedrugabsorbed.
➢Ko/w=Distributionofthedruginthe organicphase(octanol)
Distributionofthedrugintheaqueousphase………….(1.7)

93. 8)Drugstability:
➢Adrugfororalusemaydestabilizeeitherduringitsshelflifeorin
theGIT.
➢Twomajorstabilityproblemsresultinginpoorbioavailability
ofanorallyadministereddrugaredegradationofthedruginto
inactiveform,andinteractionwithoneormoredifferent
component(s)eitherofthedosageformorthosepresentintheGITto
formacomplexthatispoorlysolubleorisunabsorbable.

94. 9) Complexation and chelation

96. 1.Disintegrationtime(tablets/capsules):
➢Rapiddisintegrationisimportanttohavearapid
absorptionsolowerdisintegrationtimeisrequired.
➢Disintegrationtimeoftabletisdirectlyproportionalto–
amountofbinder&Compressionforce.
➢Invitrodisintegrationtestgivesnomeansofaguarantee
ofdrugsbioavailabilitybecauseifthedisintegrateddrug
particlesdonotdissolvethenabsorptionisnotpossible.
➢E.g.COATEDTABLETS:theyhavelongdisintegration
time.
➢Fastdispersibletabletshaveshortdisintegrationtime.
PHARMACEUTICALFACTORS

97. 2)Dissolutiontime:
➢Dissolutionisaprocessinwhichasolidsubstance
solubilisesinagivensolventi.e…masstransferfromthe
solidsurfacetotheliquidphase.
➢Dissolutiontimeisalsoanimportantfactorwhichaffect
thedrugabsorption.
3)Manufacturingvariables:
➢Severalmanufacturingprocessesinfluencedrug
dissolutionfromsoliddosageforms.
➢Forexample:Fortabletitis
✓Methodof granulation
✓Compressionforce

98. ▪Methodofgranulation:
➢Thewetgranulationprocessisthemostconventionaltechnique
➢Thetabletsthatdissolvefasterthanthosemadebyother
granulationmethods.
➢Butwetgranulationhasseverallimitationslikeformationof
crystalbridgeorchemicaldegradation.
➢Themethodofdirectcompressionforcehasbeenutilizedtoyield
thetabletsthatdissolveatafasterrate.
▪Compressionforce:
➢Thecompressionforceemployedintabletingprocessinfluence
density,porosity,hardness,disintegrationtimeanddissolutionrate
oftablets.
➢Highercompressionforceincreasesthedensityandhardnessof
thetablet,decreasesporosityandhencepenetrabilityofthesolvent
intothetabletandthusinslowingofdissolutionandabsorption
(Fig.A)

99. ➢Ontheotherhand,highercompressionforcecauses
deformation,crushingorfractureofdrugparticlesintosmaller
onesandcausesalargeincreaseineffectivesurfacearea.This
resultsinanincreaseindissolutionrateoftablets(FigB)
➢AcombinationofboththecurvesAandBisalsopossibleas
shownincurvesC&D.
Fig.Influenceofcompressionforceonthedissolutionrateoftablets

100. 4)Pharmaceuticalingredients(excipients/adjuvants):
➢MorethenumberofExcipientsinthedosageform,
morecomplexitis&greaterthepotentialforabsorption
andBioavailabilityproblems.
➢Commonlyusedexcipientsinvariousdosageformsare,
a)Vehicle:
➢Rateofabsorption–dependsonitsmiscibilitywith
biologicalfluid
➢Misciblevehiclescausesrapidabsorptione.g.propylene
glycol.
➢Immisciblevehicles–Absorptiondependsonits
partitioningfromoilphasetoaqueousbodyfluid.

101. b)Diluents:
➢Hydrophilicdiluents–ImpartsAbsorption
Hydrophobicdiluents–RetardsAbsorption
➢Also,thereisadrug-diluentinteraction,forminginsoluble
complexandretardstheabsorption. E.g.Tetracycline-DCP
c)Binders&granulatingagent:
➢Hydrophilicbinders–Impartshydrophilicpropertiestothe
granulesurface–givesbetterdissolutionproperties.E.g.
Starch,Gelatin.PVP.
➢Moreamountofbinderincreasesthehardnessofthetablet
andretardstheabsorptionrate.
d)Disintegrants:
➢Mostlyhydrophilicinnature.
➢Decreaseinamountofdisintegrants–significantlylowers
bioavailability.

102. e)Lubricants:
➢Commonlyhydrophobicinnature–thereforeinhibitspenetration of
water intotabletandthusdissolutionanddisintegration.
f)Suspendingagents/viscosityagent:
➢Stabilizedthesoliddrugparticlesandthusaffectdrugabsorption.
➢Macromoleculargumformsun-absorbable complexwithdrug e.g.
NaCMC.
➢Viscosityimparters–actasamechanicalbarriertodiffusionof
drugfromitsdosageformandretardGItransitofdrug.
g)Surfactants:
➢Mayenhanceorretardsdrugabsorptionbyinteractingwithdrug
ormembraneorboth.
➢e.g.Griseofulvin,steroids
➢Itmaydecreaseabsorptionwhenitformstheun-absorbable
complexwithdrugaboveCMC.

103. h)Coating:
➢Ingeneral,deleteriouseffectsofvariouscoatingsonthedrug
dissolutionfromatabletdosageformareinthefollowingorder.
Entericcoat>sugarcoat>non-entericcoat
➢Thedissolutionprofileofcertaincoatingmaterialschangeon
aging;e.g.shellaccoatedtablets,onprolongedstorage,dissolve
moreslowlyintheintestine.Thiscanbehowever,beprevented
byincorporatinglittlePVPinthecoatingformulation.
i)Buffers:
➢Buffersaresometimesusefulincreatingtherightatmosphere
fordrugdissolutionaswasobservedforbufferedaspirintablets.
➢However,certainbuffersystemscontainingpotassiumcations
inhibitthedrugabsorptionasseenwithVitaminB
2and
sulfanilamide.

104. j)Colorants:
➢Evenalowconcentrationofwatersolubledyecanhavean
inhibitoryeffectondissolutionrate.
➢Thedyemoleculesgetabsorbedontothecrystalfacesand
inhibitthedrugdissolution.
➢Forexample:Brilliantblueretardsdissolutionofsulfathiazole.
k)Complexingagents:
➢Complexformationhasbeenusedtoalterthephysicochemical
&biopharmaceuticalpropertiesofadrug.
▪Example
1)Enhanceddissolutionthroughformationofasolublecomplex.
➢E.g.ergotaminetartarate-caffeinecomplex&hydroquinone-
digoxincomplex.
2)Enhancedlipophilicityforbettermembranepermeability.
➢E.g.caffeine-PABAcomplex.

105. 5)Nature&typeofdosageform:
➢Apartfromtheproperselectionofthedrug,clinical
successoftendependstoagreatextentontheproper
selectionofthedosageformofthatdrug.
➢Asageneralrule,thebio-availabilityofadrugform
variousdosageformsdecreaseinthefollowingorder:
Tablets>CoatedTablets>EntericCoatedTablets
Solutions>Emulsions>Suspensions>Capsules>
>
SustainedReleaseProducts.

107. ➢6)Productage&storagecondition:
➢Productagingandstorageconditionscanadversely
affectthebio-availabilitybychangeinespeciallythe
physico-chemicalpropertiesofthedosageforms.
➢Forexample:
1.Precipitationofthedruginsolution
2.Hardeningoftablet
3.Changeinparticlesizeofsuspension.

108. C) Biological (Physiological) Factors
1)Routeofadministration:
❖Parentralroute:
➢Theyavoidthepossibilityofhepaticfirst-passmetabolism.

109. •Intra-arterial:
➢Intra-arterialinjectionisusedtodeliverdrugsdirectlyto
organs,forexample,incancerchemotherapy,andintheuseof
vasopressinforGIbleeding.
•Intrathecal:
➢Injectiondirectlyintothecerebrospinalfluid(CFS)ensures
completeCNSbioavailabilityfordrugsthatcannotcrossthe
blood-brainbarrier.
➢E.g.Mepivacaineandprilocaineforspinalanesthesia.
•Intravenous(IV):
➢IVadministrationintroducesdrugdirectlyintothevenous
circulation.
➢IVbolusisusedforimmediatetherapeuticeffect,typicallyfor
general anesthesiaandfortreatmentofcardiacarrhythmia.

110. •Intramuscular(IM):
➢Intramuscularinjection
vaccinesthatarenot
isusedmainlyfor
absorbedorally,for
drugsand
example,
aminoglycosides,insulin,andhepatitisvaccine.
➢TheIMrouteisoftenusedforsustainedmedicationand
specializedvehicles,suchasaqueoussuspensions,oily
vehicles
❖Topicalroute:
•Transdermal:
➢Thisdrugdeliveryrouteincludecontinuousreleaseofdrug
overaspecifiedperiod,lowpresystemicclearance,andfacile
drugwithdrawalbysimplyremovingthedevice,andgood
patientconvenienceandcompliance.

111. ➢Somedisadvantagesrelatetobarrierpropertiesoftheskin,skin
reactions,andtherelativelylargedosesize.
➢Gnerallysmalldoseisdeleverd(<10mg)
➢E.gclonidine,estradiol
•Intranasal:
➢Intranasaladministrationmaybeusedforlocalorsystemiceffects.
Localeffectsincludetreatmentofnasalallergies,rhinitis,andnasal
congestion.Nasaldeliveryforsystemiceffectsisestablishedfora
smallnumberofdrugs
➢E.g.Vasopressinanaloguesandoxytocinarecommercially
availableforintranasaldosage.
•Vaginal:
➢Vaginaldrugdeliveryisusedmostlyforlocaleffects,butvaginal
absorptioncangiverisetorapidandefficientsystemicdelivery.
➢E.g.vaginalringsandbiodegradablemicrospheres.

112. ❖Enteralroutes:
•Rectal:
➢Rectalabsorptionisgenerallyslowerthanoralabsorption,butfor
somedrugs,rectalabsorptionexceedsoralabsorptionpresumably
duetoavoidanceoffirst-passmetabolismafterrectaldelivery.
➢E.g.Metoclopramide,ergotamine,lidocaine
•Buccal:
➢Drugscanbeabsorbedfromtheoralcavityitselforsublingually.
Absorptionfromeitherrouteisrapid,sublingualmoresoapparently
becauseofgreaterpermeabilityofsublingualmembranesandrich
bloodsupply.
➢ThemeanpHofsalivaisapproximately6sothatdrugabsorption,
predominantlypassiveinnature,isfavoredforunchanged
molecules,acidswithpKavalues>3,andbaseswithpKavalues<9.
➢E.g.organicnitrates,barbiturates,papaverine,prochlorperazine,
benzodiazepines.

113. 2)Membranephysiology:
➢Thecellmembraneconsistsofglobularproteinsembeddedina
dynamicfluid,lipidbilayermatrix
➢Cellmembranesaregenerallythin,approximately70to100Å
inthickness.
➢Cellmembranesarecomposedprimarilyofphospholipidsin
theformofabilayerinterdispersedwithcarbohydratesand
proteingroups.Theplasmamembranetobecomposedoftwo
layersofphospholipidbetweentwosurfacelayersofproteins,
withthehydrophilic"head"groupsofthephospholipidsfacing
theproteinlayersandthehydrophobic"tail"groupsofthe
phospholipidsalignedintheinterior.
➢lipid-solubledrugstendtopenetratecellmembranesmore
easilythanpolarmolecules.
➢proteinsprovideapathwayfortheselectivetransferofcertain
polarmoleculesandchargedionsthroughthelipidbarrier.

114. 3)Age:
➢Ininfants,thegastricpHishighandintestinalsurfaceand
bloodflowtotheGITislowresultinginalteredabsorption
patternincomparetoadults.
➢Inelderlypersons,gastricemptyingaltered,decreased
intestinalsurfaceareaandGIbloodflow,higherincidentsof
achlorhydriasoimpaireddrugabsorption.
4)Gastricemptyingtime:
➢Theprocessbywhichfoodleavesthestomachandenters the
duodenum.
➢Rapidgastricemptyingisrequiredwhenthedrugisbest
absorbedfromdistalpartofthesmallintestine.

115. ➢Delayedgastricemptyingisrequiredwhendrugsareabsorbed
fromproximalpartofthesmallintestineandprolongeddrug
absorptionsitecontactisdesired.
➢Gastricemptyingisafirstorderprocess.
1.Gastricemptyingrate:Thisisthespeedatwhichthe
stomachcontentsemptyintotheintestine.
2.Gastricemptyingtime:Whichisthetimerequired
forthegastriccontentstotheSMALLINTESTINE.
3.Gastricemptyinghalf-life:whichisthetimetakenfor
halfthestomachcontentstoempty.

116. VolumeofIngested
Material
Asvolumeincreasesinitiallyanincreasethena
decrease.Bulkymaterialtendstoemptymoreslowly
thanliquids
TypeofMeal Gastricemptyingrate:
carbohydrates>proteins>fats
Physicalstateof
gastriccontents
Solutionsorsuspensionsofsmallparticlesempty
morerapidlythandochunksofmaterialthatmust
bereducedinsizepriortoemptying.
BodyPosition Lyingontheleftsidedecreasesemptyingrateand
rightsidepromotesit
Drugs
Anticholinergics
Narcoticanalgesics
Ethanol
Reductioninrateofemptying
Reductioninrateofemptying
Reductioninrateofemptying
EmotionalstateAnxietypromoteswhereasdepressionretardsit
Diseasestates gastriculcer,hypothyroidismretardsit,while
duodenalulcer,hyperthyroidismpromotesit.

117. 5)Intestinaltransittime:
➢Intestinaltransittimeisthemajorsiteofabsorptionofmostof
drugs.
➢Themixingmovementoftheintestinethatoccursdueto
peristalticcontractionspromotesdrugabsorption,firstly,by
increasingthedrugintestinalmembranecontactandsecondlyby
enhancingdrugdissolutionofespeciallyofpoorlysolubledrugs,
throughinducedagitation.
➢Delayedintestinaltransitisdesirablefor
A)Drugsthatdissolveorreleaseslowlyfromtheirdosageform
(sustainedreleaseproducts)
B)Drugsthatdissolveonlyinintestine(entericcoated
formulations)
C)Drugsabsorbed fromspecificsitesintheintestine(severalB
vitamins)

118. Intestinalregion Transittime
Duodenum 5minutes
Jejunum 2 hours
Ileum 3 to 6hours
Caecum 0.5 to 1hour
Colon 6 to 12hours
➢Intestinaltransittimeisinfluencedbyvariousfactorssuchas
food,diseasesanddrugs
➢E.g.metoclopramidewhichpromotesintestinaltransit,enhance
absorptionofrapidlysolubledrugswhileanticholinergicretards
intestinaltransitandpromotestheabsorptionofpoorlysoluble
drugs.

119. 6)
Gastrointestinal
pH:

120. 7)Diseasestates:
Gastricdiseases(Achlorhydricpatients):
➢Theymaynothaveadequateproductionofacidsinthestomach;
stomachHClisessentialforsolubilizinginsolublefreebases.
➢Manyweak-basedrugsthatcannotformsolublesalts&remain
undissolvedthereforeunabsorbed.Saltformsofthesedrugs
cannotbepreparedbecausethefreebasereadilyprecipitatesout.
➢E.g.Dapsone,itraconazole,andketoconazole.
Cardio-vasculardiseases:
➢Severalchangesassociatedwithcongestivecardiacfailure
influencebio-availabilityofadrugviz.,edemaoftheintestine,
decreasedbloodflowtotheGITandgastricemptyingrateand
alteredGIpH,secretionsandmicrobialflora.

121. 8)BloodflowthroughtheGIT:
➢Itplaysamajorroleinabsorptionbycontinuouslymaintain
theconcentrtiongradientacrosstheepithelialmembrane.
➢TheGITisextensivelysupplied byblood capillarynetwork.
➢Bloodflowisimpforactivelyabsorptionofdrugs.
➢Absorptionofpolarmoleculesdoesn’tdependsonthe
flowbutlipidsolublemoleculeshighlydependsonthe
flow.
blood
blood
➢FoodinfluencesbloodflowtotheGIT.Perfusionincreases
aftermeals&persistforfewhoursbutabsorptionisnot
affected.

122. 9)Gastrointestinalcontents:
1)Food-druginteractions:ThepresenceoffoodintheGItract
canaffectthebioavailabilityofthedrug.
➢Digestedfoodscontainaminoacids,fattyacids,andmany
nutrientsthatmayaffectintestinalpHandsolubilityofdrugs.
➢Someeffectsoffoodonthebioavailabilityofadrugfroma
drugproductinclude:
Delayingastricemptying
Stimulationofbileflow
AchangeinthepHoftheGItract
Anincreaseinsplanchnicbloodflow

123. ➢Presenceoffoodwillaffectabsorptioninfollowingway
a)Decreasedabsorption:ex.Penicillin,erythromycin,ethanol,
tetracycline,levodopaetc.
b)Increasedabsorption:exgrieseofulvin,diazepam,vitaminsetc.
2)Fluidvolume:
➢Largefluidvolumeresultsinbetterdissolution,rapidgastric
emptyingandenhancedabsorption-
➢Ex.Erythromycinisbetterabsorbedwhentakenwithaglassof
waterunderfastingconditionthanwhen takenwithmeals.
3)InteractionofdrugwithnormalGIconstituents:
➢TheGITcontainsanumberofnormalconstituentssuchasmucin
whichisaprotectivemucopolysaccharidesthatlinestheGImucosa,
interactwithstreptomycin.

124. 10)Presystemicmetabolism:
➢Thelossofdrugsthroughbio-transformationbysucheliminating
organsduringthepassagetosystemiccirculationiscalledasfirst-
passorpre-systemicmetabolism.
➢completeabsenceofthedruginplasmaafteroraladministrationis
indicativeofthefirst-passeffects.Thefourprimarysystemswhich
affectthepre-systemicmetabolismofadrug
1)LumenalEnzymes
2)Gutwall enzymes/mucosalenzymes
3)Bacterialenzymes
4)Hepaticenzymes

125. 1)LumenalEnzymes:
➢Theprimaryenzymefoundingastricjuiceispepsin.Lipases,
amylasesandproteasesaresecretedfromthepancreasintothe
smallintestineinresponsetoingestionoffood.
➢Pepsinsandtheproteasesareresponsibleforthedegradationof
proteinandpeptidedrugsinthelumen.
2)Gutwallenzymes:
➢Thesealsocalledmucosalenzymes,theyarepresentinstomach,
intestineandcolon.Alcoholdehydroginase(ADH)isanenzyme
ofstomachmucosathatinactivatesethanol.
➢E.g.sulfationofethinylestrdiol&isoprenaline.

126. 3)Bacterialenzymes:
➢Whicharemainlylocalizedwithinthecolonicregion
ofthegastrointestinaltract,alsosecreteenzymes
whicharecapableofarangeofreactions.
➢E.g.Sulphasalazine,isaprodrugof5-aminosalicylic
acidlinkedviaanazobondtosulphapyridine.

127. 4)Hepaticenzymes:
➢Severaldrugsundergofirst–passhepaticmetabolism,thehighly
extractedonesbeingIsoprenaline,propanolol,diltiazem,etc.

128. ❖REFERENCE:-
1.BrahmankarD.M.,JaiswalS.B.,Firstedition,“Absorptionof
Drugs”BiopharmaceuticsandPharmacokinetics–Atreatise,
VallabhPrakashan,Delhi1995.
2.ShargelL.,AndrewB.C.,Fourthedition“Physiologicfactors
relatedtodrugabsorption”AppliedBiopharmaceuticsand
Pharmacokinetics,PrenticeHallInternational,INC.,Stanford1999.
3.AultonM.E.Pharmacetutics“TheScienceofDosageForm
Design”,2
ndEd.;ChurchillLivingstone.
4.SwarbrickJ.,BoylanJ.C.,“Absorption”Encyclopediaof
PharmaceuticalTechnology,ThirdEditionMarcelDekker,INC.,
NewYork1988:1:1-32.
5.Biopharmaceutics&pharmacokineticsbyG.R.Chatwal.
6.Humananatomy&physiologybyTortora.