Pharmacokinetics

ADME

1. Department of Pharmacology

2. ABSORPTION

3. •Absorptionismovementofthedrugfromitssiteof
administrationintothecirculation.
•Notonlythefractionoftheadministereddosethatgetsabsorbed,
butalsotherateofabsorptionisimportant.
•Exceptwhengiveni.v.,thedrughastocrossbiological
membranes;absorptionisgovernedbytheabovedescribed
principles
•Mostofdrugsareabsorbedbythewayofpassivetransport

4. Factors affectingabsorption
•Drugproperties:Lipidsolubility,molecularweightandpolarity
•Bloodflowtotheabsorptionsite
•Totalsurfaceareaavailableforabsorption
•Contacttimeattheabsorptionsurface
•Affinitywithspecialtissue

5. Aqueoussolubility
•Drugsgiveninsolidformmustdissolveintheaqueousbiophase
beforetheyareabsorbed.
•Forpoorlywatersolubledrugs(aspirin,griseofulvin)rateof
dissolutiongovernsrateofabsorption.
•KetoconazoledissolvesatlowpH:gastricacidisneededforits
absorption.
•Obviously,adruggivenaswaterysolutionisabsorbedfasterthan
whenthesameisgiveninsolidformorasoilysolution.
Concentration
•Passivediffusiondépendsonconcentrationgradient;druggiven
asconcentratedsolutionisabsorbedfasterthanfromdilute
solution.

6. Areaofabsorbingsurface
•Largeristhesurfacearea,fasteristheabsorption.
Vascularityoftheabsorbingsurface
•Bloodcirculationremovesthedrugfromthesiteofabsorption
andmaintainstheconcentrationgradientacrosstheabsorbing
surface.
•Increasedbloodflowhastensdrugabsorptionjustaswind
hastensdryingofclothes.
Routeofadministration
•Thisaffectsdrugabsorption,becauseeachroutehasitsown
peculiarities.

7. Routeofadministration
Topical
•Dependsonlipidsolubility–onlylipidsolubledrugsare
penetrateintactskin–onlyfewdrugsareused
therapeutically
•Examples–GTN,Hyoscine,Fentanyl,Nicotine,testosterone
andestradiol
•Organophosphorouscompounds–systemictoxicity
•Abradedskin:tannicacid–hepaticnecrosis
•Corneapermeabletolipidsolubledrugs
•Mucusmembranesofmouth,rectum,vaginaetc,are
permeabletolipophillicdrugs

8. SubcutaneousandIntramuscular
•Drugsdirectlyreachthevicinityofcapillaries–passescapillary
endotheliumandreachcirculation
•Passesthroughthelargeparacellularpores
•Fasterandmorepredictablethanoralabsorption
•Exerciseandheat–increaseabsorption
•Adrenaline–decreaseabsorption

9. OralRoute
Physicalproperties–Physicalstate,lipidorwatersolubility
Dosageforms
Particlesize
DisintegrationtimeandDissolutionRate
Formulation–Biopharmaceutics
Physiologicalfactors
Ionization,pHeffect
PresenceofFood
PresenceofOtheragents
Firstpassmetabolism
Beforethedrugreachesthesystemiccirculation,thedrugcanbe
metabolizedintheliverorintestine.
AsaResult,theconcentrationofdruginthesystemiccirculationwill
bereduced.

11. •Intravenousadministrationhasnoabsorptionphase
•Accordingtotherateofabsorption
•Inhalation→Sublingual→Rectal→intramuscular→subcutaneous→
oral→transdermal
•Example–NitroglycerineIVeffect–immediate,Sublingual–1to3min
andperrectal–40to60min

12. Bioavailability
•Bioavailabilityreferstotherateandextentofabsorptionofadrug
fromdosageformasdeterminedbyitsconcentration-timecurvein
bloodorbyitsexcretioninurine.
•Itisameasureofthefraction(F)ofadministereddoseofadrug
thatreachesthesystemiccirculationintheunchangedform.
•Bioavailabilityofdruginjectedi.v.is100%,butisfrequentlylower
afteroralingestion,because:
Thedrugmaybeincompletelyabsorbed
Theabsorbeddrugmayundergofirstpassmetabolismin
intestinalwalland/orliverorbeexcretedinbile.
Incompletebioavailabilityafters.c.ori.m.injectionisless
common,butmayoccurduetolocalbindingofthedrug

14. Bioavailability -AUC
Plasma
concentration
(mcg/ml
)
0
5
Time
(h)
1
0
1
5
AUCp.o.
F = ------------x 100%
AUCi.v.
AUC –area underthe curve
F –bioavailability
MTC
MEC

15. Bioequivalence
•Oralformulationsofadrugfromdifferentmanufacturersor
differentbatchesfromthesamemanufacturermayhavethesame
amountofthedrug(chemicallyequivalent)butmaynotyieldthe
samebloodlevels—biologicallyinequivalent.
•Twopreparationsofadrugareconsideredbioequivalentwhentherate
andextentofbioavailabilityoftheactivedrugfromthemisnot
significantlydifferentundersuitabletestconditions.
•Beforeadrugadministeredorallyinsoliddosageformcanbe
absorbed,itmustbreakintoindividualparticlesoftheactivedrug
(disintegration).

16. •Differencesinbioavailabilityareseenmostlywithpoorlysolubleand
slowlyabsorbeddrugs.
•Reductioninparticlesizeincreasestherateofabsorptionofaspirin
(microfinetablets).
•Theamountofgriseofulvinandspironolactoneinthetabletcanbe
reducedtohalfifthedrugparticleismicrofined.
•Thereisnoneedtoreducetheparticlesizeoffreelywatersoluble
drugs,e.g.paracetamol.

18. DISTRIBUTION

19. •ReversibleTransferofaDrugbetweentheBloodandtheExtra
VascularFluidsandTissuesofthebody(Eg:fat,muscleandbrain
tissue)
•Onceadrughasgainedaccesstothebloodstream,itgetsdistributedto
othertissuesthatinitiallyhadnodrug,concentrationgradientbeingin
thedirectionofplasmatotissues.
•Theextentandpatternofdistributionofadrugdependsonits
Lipidsolubility
IonizationatphysiologicalpH(afunctionofitspKa)
Extentofbindingtoplasmaandtissueproteins
Presenceoftissue-specifictransporters
Differencesinregionalbloodflow.

20. •Movementofdrugproceedsuntilanequilibriumisestablished
betweenunbounddrugintheplasmaandthetissuefluids.
•Subsequently,thereisaparalleldeclineinbothduetoelimination.

23. Apparentvolumeofdistribution(V)
•Presumingthatthebodybehavesasasinglehomogeneous
compartmentwithvolume(V)intowhichthedruggets
immediatelyanduniformlydistributed
•“Thevolumethatwouldaccommodateallthedruginthebody,if
theconcentrationthroughoutwasthesameasinplasma”

24. •Fluidvolumethatisrequiredtocontaintheentiredruginthebodyat
thesameconcentrationmeasuredintheplasma.
•Calculatedbydividingthedosethatultimatelygetsintothesystemic
circulationbytheplasmaconcentrationattimezero(C
0)
V
d= Amount of drug in body/Plasma concentration at time zero (C
0)
•If500mgofdrugreachescirculation…(totalamountofdrug)andif
plasmaconcentrationis0.5mg/ml.Vdwillbe500/0.5=1000ml.
•Whichmeansyourequire1000mloffluidtoaccommodatetotal500
mgofdrugatconcentrationof0.5mg/ml.
•Attimesitcanbelargerthantotalbloodvolume.(whendrughas
beenstoredinperipheraltissuessolowerbloodconcentration).
•Attimesitcanbesmallerthanorequaltototalbloodvolume(when
drugremainsinvascularcompartment)

25. Distribution into the water compartments of body

27. Plasmacompartment
•Drugshavinghighmolecularweightorextensivelyplasmaprotein
boundlikeheparinV
d=4L
Extracellularfluid
•Lowmolecularweightbuthydrophilicdrugs–Aminoglycosides
V
d=14L
Totalbodywater
•Lowmolecularweightandlipophilic,–E.gEthanolV
d=42L
Chloroquine–13000 L
Digoxin –420 L
Morphine –250 L
Propranolol –280L
Streptomycin and
Gentamicin –18L

28. Plasmaproteinbinding
•Mostdrugspossesphysicochemicalaffinityforplasmaproteins
Acidicdrugsbindtoplasmaalbumin,basicdrugsbindto
alpha-1--acidglycoprotein
Reversiblemanner
Extensivebindingservesasacirculatingdrugreservoir
Otherproteinstowhichdrugscanbindglobulins,
transferrin,ceruloplasmin,tissueproteins&
nucleoproteins

30. Clinicalimplicationsofplasmaproteinbinding
1.Highlyplasmaproteinbounddrugsdoesnotcrossmembranesso
largelyrestrictedtovascularcompartments(smallerV
d).
2.Temporarystorageofthedrugwhichisnotavailableforany
action.
3.Highdegreeofproteinbindinggenerallymakesthedruglong
acting
4.Plasmaconcentrationsofthedrugrefertoboundaswellasfree
drug.
5.Onedrugcanbindtomanysitesonthealbuminmolecule.
Conversely,morethanonedrugcanbindtothesamesite.

31. 6.Displacementreactions-(Druginteractions)–Salicylatesdisplace
sulfonylureas&methotrexate.–Indomethacin,phenytoindisplace
warfarin.–SulfonamidesandvitKdisplacebilirubin(kernicterus
inneonates).
7.Inhypoalbuminemia,reducedbindingleadstohighconcentrations
offreedruge.g.phenytoinandfurosemide.
8.Otherdiseases:e.g.phenytoinandpethidinebindingisreducedin
uraemia

32. ClinicalimplicationsofVolumeofDistribution
•DialysisisnotveryusefulfordrugswithhighVde.gdigoxin,
imipramine
•Ithelpsinestimatingthetotalamountofdrugatanytime
•Vdisimportanttodeterminetheloadingdose
Loading dose= VdX desired concentration
Amount of drug = VdX plasma concof drug at certain time

34. Redistribution
•Highlylipid-solubledrugsgetinitiallydistributedtoorganswith
highbloodflow(brain,heart,kidney)&laterintobulkyless
vasculartissues(muscle,fat)
•Soplasmaconcentrationfallsandthedrugiswithdrawnfrom
thesesites
•Ifthesiteofactionofdrugisoneofhighlyperfusedorgans,
redistributionmayresultinterminationofdrugaction.
•Greaterthelipidsolubilityfasteristheredistributionofdrug.
•Anaestheticactionofthiopentonesod.injectedi.v.isterminatedin
fewminutesduetoredistribution.
•Toovercome,givecontinuousinfusion

36. Plasma Half Life

38. Blood Brain Barrier

39. FunctionsandPropertiesoftheBBB
•Protectsthebrainfrom"foreignsubstances"inthebloodthatmay
injurethebrain.
•Protectsthebrainfromhormonesandneurotransmittersinthe
restofthebody.
•Maintainsaconstantenvironmentforthebrain.
PropertiesofdrugsthatcancrossBBB
•Lowmolecularweight
•Highdegreeoflipidsolubility
•Nonionized
•TertiarystructureandFreedrug

40. PlacentalBarrier
•Lipoidalandallowsfreepassageoflipophilicdrugs
•P-Glycoproteinlimitsexposuretomaternallyadministereddrugs
•Alsoplacentaissiteofmetabolism-lowersexposuretodrugs
•Incompletebarrier
•Congenitalanomalies

43. WhatisBiotransformation(Metabolism)?
•Chemicalalterationofthedruginthebody
•Toconvertnon-polarlipidsolublecompoundstopolarlipid
insolublecompoundstoavoidreabsorptioninrenaltubules
•Mosthydrophilicdrugsarelessbiotransformedandexcreted
unchanged–streptomycin,neostigmineandpancuronium
•Biotransformationisrequiredforprotectionofbodyfromtoxic
metabolites

44. ResultsofBiotransformation
1.Activedruganditsmetabolitetoinactivemetabolites–most
drugs(Ibuprofen,paracetamol,chlormphenicol)
2.Activedrugtoactiveproduct(phenacetin–acetminophen/
paracetamol,morphinetoMorphine-6-glucoronide,digitoxinto
digoxin)
3.Inactivedrugtoactive/enhancedactivity(prodrug)–levodopa-
carbidopa,prednisone–prednisoloneandenalapril–enalaprilat)
4.Notoxicorlesstoxicdrugtotoxicmetabolites(Isonizideto
Acetylisoniazide)

45. •Theprimarysitefordrugmetabolismisliver;othersare—kidney,
intestine,lungsandplasma.
•Biotransformationofdrugsmayleadtothefollowing
Inactivation
Activemetabolitefromanactivedrug
Activationofinactivedrug

46. 1.Nonsynthetic/Phase-I/
Functionalizationreactions
Afunctionalgroupisgeneratedorexposed,
metabolitemaybeactiveorinactive.
2.Synthetic/Conjugation/PhaseII
reactions:
•Anendogenousradicalisconjugatedto
thedrugmetaboliteismostlyinactive;
exceptfewdrugs.
•e.g.glucuronideconjugateofmorphine
andsulfateconjugateofminoxidilare
active.
Biotransformation -Classification

47. Mostimportantdrugmetabolizingreaction–additionofoxygen
or(–ve)chargedradicalorremovalofhydrogenor(+ve)charged
radical.
Variousoxidationreactionsare–oxygenationorhydroxylationofC-,
N-orS-atoms;NorO-dealkylation.
Examples–Barbiturates,phenothiazines,paracetamolandsteroids.
Involve–cytochromeP-450monooxygenases(CYP),NADPH
(NicotinamideAdenineDinucleotidePhosphate)andoxygen
Morethan100cytochromeP-450isoenzymesareidentifiedand
groupedintomorethan20families–1,2and3…Sub-familiesare
identifiedasA,B,andC
Phase I -Oxidation

48. Inhuman-only3isoenzymefamiliesimportant–CYP1,CYP2and
CYP3
CYP3A4/5carryoutbiotransformationoflargestnumber(30–50%)of
drugs.Inadditiontoliver,thisisoformsareexpressedinintestine
(responsibleforfirstpassmetabolismatthissite)andkidneytoo
InhibitionofCYP3A4byerythromycin,clarithromycin,ketoconzole,
itraconazole,verapamil,diltiazemandaconstituentofgrapefruitjuice
isresponsibleforunwantedinteractionwithterfenadineand
astemizole,rifampicin,phenytoin,carbmazepine,phenobarbitalare
inducersoftheCYP3A4

50. NonmicrosomalEnzymeOxidation
Some Drugs are oxidized by non-microsomalenzymes (mitochondrial
and cytoplsmic) –Alcohol, Adrenaline, Mercaptopurine
Alcohol –Dehydrogenase
Adrenaline –MAO andCOMT
Mercaptopurine–Xanthineoxidase
Phase I –Reduction
This reaction is conversed of oxidation and involves CYP 450 enzymes
working in the oppositedirection.
Examples -Chloramphenicol, levodopa, halothane andwarfarin
Levodopa(DOPA)
Dopamine
DOPA-decarboxylase

51. Cyclization:isformationofringstructurefromastraightchaincompound,
e.g.proguanil.
Decyclization:isopeningupofringstructureofthecyclicmolecule
e.g.phenytoin,barbiturates
PhaseI–Hydrolysis
Thisiscleavageofdrugmoleculebytakingupofamoleculeofwater.
Similarlyamidesandpolypeptidesarehydrolyzedbyamidaseand
peptidases.
Hydrolysisoccursinliver,intestines,plasmaandothertissues.
Examples-Cholineesters,procaine,lidocaine,pethidine,oxytocin

52. Phase IImetabolism
ConjugationofthedrugoritsphaseImetabolitewithanendogenous
substrate-polarhighlyionizedorganicacidtobeexcretedinurineor
bile-highenergyrequirements
Glucoronideconjugation-mostimportantsyntheticreaction
Compoundswithhydroxylorcarboxylicacidgroupareeasily
conjugatedwithglucoronicacid-derivedfromglucose
Examples:Chloramphenicol,aspirin,morphine,metroniazole,
bilirubin,thyroxine
Drugglucuronides,excretedinbile,canbehydrolyzedinthegutby
bacteria,producingbeta-glucoronidase-liberateddrugis
reabsorbedand undergoesthesamefate-enterohepatic
recirculation(e.g. chloramphenicol,phenolphthalein,oral
contraceptives)andprolongstheiraction

53. Acetylation:Compoundshavingaminoorhydrazineresiduesare
conjugatedwiththehelpofacetylCoA,e.g.sulfonamides,isoniazid
Geneticpolymorphism(slowandfastacetylators)
Sulfateconjugation:Thephenoliccompoundsandsteroids are
sulfatedbysulfokinases,e.g.chloramphenicol,adrenalandsexsteroids
Methylation:Theaminesandphenolscanbemethylated.Methionine
andcysteineactasmethyldonors.Examples:adrenaline,histamine,
nicotinicacid.
Ribonucleoside/nucleotidesynthesis:activationofmanypurineand
pyrimidineantimetabolitesusedincancerchemotherapy.

54. Factorsaffectingbiotransformation
Concurrentuseofdrugs:Inductionandinhibition
Geneticpolymorphism
Pollutantexposurefromenvironmentorindustry
Pathologicalstatus
Age

55. EnzymeInhibition
•Onedrugcaninhibitmetabolismofother–ifutilizessameenzyme
•Howevernotcommonbecausedifferentdrugsaresubstrateof
differentCYPs
•Adrugmayinhibitoneisoenzymewhilebeingsubstrateofother
isoenzyme–quinidine
•Someenzymeinhibitors–Omeprazole,metronidazole,isoniazide,
ciprofloxacinandsulfonamides

57. EnzymeInduction
CYP3A–antiepilepticagents-Phenobarbitone,Rifampicinand
glucocorticoide
CYP2E1-isoniazid,acetone,chronicuseofalcohol
Otherinducers–cigarettesmoking,charcoalbroiledmeat,industrial
pollutants–CYP1A
ConsequencesofInduction:
•Decreasedintensity–FailureofOralContraceptivePills
•Increasedintensity–Paracetamolpoisoning
•Tolerance–Carbmazepine
•Someendogenoussubstratesaremetabolizedfaster–
steroids,bilirubin

60. OrgansofExcretion
Excretionisatransportprocedurewhichtheprototypedrug(or
parentdrug)orothermetabolicproductsareexcretedthrough
excretionorganorsecretionorgan
Hydrophiliccompoundscanbeeasilyexcreted.
Routesofdrugexcretion
Kidney
Biliaryexcretion
Sweatandsaliva
Milk
Pulmonary

63. HepaticExcretion
•Drugscanbeexcretedinbile,especiallywhentheareconjugatedwith
–glucuronicAcid
•Drugisabsorbed
•Glucuronidatedorsulfatatedintheliverandsecretedthroughthebile
•Glucuronicacid/sulfateiscleavedoffbybacteriainGItract
•Drugisreabsorbed(steroidhormones,rifampicin,amoxycillin,
contraceptives)
•Anthraquinone,heavymetals–directlyexcretedincolon

65. RenalExcretion
GlomerularFiltration
TubularReabsorption
TubularSecretion

66. GlomerularFiltration
NormalGFR–120ml/min
Glomerularcapillarieshaveporeslargerthanusual
Thekidneyisresponsibleforexcretingofallwatersoluble
substances
Allnonproteinbounddrugs(lipidsolubleorinsoluble)presentedto
theglomerulusarefiltered
Glomerularfiltrationofdrugsdependsontheirplasmaprotein
bindingandrenalbloodflow-Proteinbounddrugsarenotfiltered!
Renalfailureandagedpersons

67. TubularReabsorption
BackdiffusionofDrugs(99%)–lipidsolubledrugsDependsonpHof
urine,ionizationetc.
Lipidinsolubleionizeddrugsexcretedasitis–aminoglycoside
(amikacin,gentamicin,tobramycin)
ChangesinurinarypHcanchangetheexcretionpatternofdrugs
•Weakbasesionizemoreandarelessreabsorbedinacidicurine.
•Weakacidsionizedmoreandarelessreabsorbedinalkalineurine
Utilizedclinicallyinsalicylateandbarbituratepoisoning–alkanized
urine(DrugswithpKa:5–8)
Acidifiedurine–atropineandmorphineetc.

68. TubularSecretion
Energydependentactivetransport–reducesthefreeconcentrationof
drugs–further,moredrugdissociationfromplasmabinding–again
moresecretion(proteinbindingisfacilitatoryforexcretionforsome
drugs)

70. Bidirectionaltransport–BloodVstubularfluid
Utilizedclinically–penicillinVsprobenecid,probenecidVsuricacid
(salicylate)
Quinidinedecreasesrenalandbiliaryclearanceofdigoxinbyinhibiting
effluxcarrierP-gp
Acidicurine
Alkalinedrugseliminated
Aciddrugsreabsorbed
Alkalineurine
Aciddrugseliminated
Alkalinedrugsabsorbed

71. Kinetics of Elimination
Clearance:Theclearance(CL)ofadrugisthevolumeofplasmafrom
whichdrugiscompletelyremovedinunittime
RenalClearancemaybecalculatedfromtheplasmaorblood
concentration(C
P),theurinaryconcentration(C
U)andtherateofflowof
urine(F
U),bytheequation.
Clearancebyaspecificorganforex.,livertheclearanceofadrugcanbe
calculatedfrom

72. FirstOrderKinetics(exponential):Rateofeliminationisdirectly
proportionaltodrugconcentration,CLremainingconstant
Constantfractionofdrugiseliminatedperunittime
ZeroOrderkinetics(linear):Therateofeliminationremainsconstant
irrespectiveofdrugconcentration
CLdecreaseswithincreaseinconcentration
Alcohol,theophyline,tolbutmide
Plasmahalf-life
•Definedastimetakenforitsplasmaconcentrationtobereducedtohalf
ofitsoriginalvalue–2phasesrapiddecliningandslowdeclining
•t
1/2=In2/k
•In2=naturallogarithmof2(0.693)
•k=eliminationrateconstant=CL/V;V=doseofIV/C
•t
1/2=0.693xV/CL

73. TargetLevelStrategy
Lowsafetymargindrugs(anticonvulsants,antidepressants,Lithium,
Theophyllineetc.–maintainedatcertainconcentrationwithin
therapeuticrange
Drugswithshorthalf-life(2-3Hrs)–drugsareadministeredat
conventionalintervals(6-12Hrs)–fluctuationsaretherapeutically
acceptable
Longactingdrugs
Loadingdose:Singledoseorrepeateddoseinquick
succession–toattaintargetconc.Quickly
Maintenancedose:dosetoberepeatedatspecificintervals
Loadingdose=targetCpXV/F

74. MonitoringofPlasmaconcentration
Usefulin
Narrowsafetymargindrugs–digoxin,anticonvulsants,
antiarrhythmicsandaminoglycosidesetc
Largeindividualvariation–lithiumandantidepressants
Renalfailurecases
Poisoningcases
Notusefulin
Responsemesurabledrugs–antihypertensives,diuretics
Drugsactivatedinbody–levodopa
Hitandrundrugs–Reseprpine,MAOinhibitors
Irreversibleactiondrugs–Orgnophosphorouscompounds

75. ProlongationofDrugaction
Byprolongingabsorptionfromthesiteofaction–Oraland
parenteral
Byincreasingplasmaproteinbinding
Byretardingrateofmetabolism
Byretardingrenalexcretion