The4PhasesofPharmacokinetics

PharmacokineticsandPharmacogenomics:
ClinicalImplications

Absorption
Distribution
Metabolism
Excretion

ElizabethA.VandeWaa,Ph.D.
Lecturer,BarkleyandAssociates
Professor,UniversityofSouthAlabama

Pharmacokinetics

Absorption
PharmaceuticalFactors
Rateofdissolution
Lipidsolubility
Route

Clinician/PatientFactors
Surfacearea
Bloodflow
Route
Competition

Absorption
Theliberationphaseextends
fromthetimeofdrug
administrationtothepoint
wherethedrugisdissolvedin
bodyfluidsandreadyfor
absorption.Absorptionisthe
processofdrugmovement
fromtheabsorptionsiteacross
oneormorecellmembrane
barriersintothecirculation.
Themostcommonmechanism
fordrugabsorptionisPASSIVE
DIFFUSION.

PhysiologicFactorsAffecting
Absorption
Firstpasseffect(presystemic metabolism)
Duringtheprocessofdrugabsorptionfromthe
gastrointestinal(GI)tract,therearetwopotential
sitesformetabolismofthedrugtooccur:1)gut
wall,and2)liver.Ifthedrugismetabolized
(chemicallyaltered)asitpassesthrougheitherof
thesesites,itissaidtoundergofirstpass
metabolism.Effectively,thedrughasbeen
metabolizedbeforeiteverreachesthesystemic
circulation.

PhysiologicFactorsAffecting
Absorption
Firstpasseffect(presystemic metabolism)
Somedrugsaresoextensivelymetabolizedwhen
takenorallythattherapeuticeffectscannotbe
obtained,e.g.,lidocaine.Thesedrugsmustbe
givenbyinjection.Otherdrugsmustbegivenin
verylargedosesorally,comparedtoparenteral
doses,toachievetherapeuticeffects;e.g.
propranololperos (PO)10to30mgeverysixto
eighthours(antihypertensive),intravenous1to
3mg(antiarrhythmic).

ClinicalRelevanceAbsorption

PharmacokineticFactors
AffectingAbsorption
ElevationofgastricpHbyantacids
Increasestheabsorbanceofbasicdrugs;
decreasesthatofacidicdrugs

Laxatives
IncreaseperistalsisanddecreaseGItransittime

Drugsthatareconstipatingmayincrease
absorptionofothermeds
Adsorbents
DrugsthatdecreaseGIbloodflow

Distribution

Maychangeoverthelifespan
Presystemic metabolismisconsideredwhen
drugsaredeveloped.
Highlyroutedependent
ViathePOroute,makesurethepatientis
awareoftheemptystomachrule,ANDthat
itappliestoantacids,antidiarrheals

Bloodflowtotissues
Barrierstodistribution

FactorsDeterminingDrugDistribution

FactorsDeterminingDrugDistribution

1. Bloodflowtotissues(perfusion)

2. Bindingofdrugtoplasmaprotein

Rapidlyperfusedtissues,suchastheheart,liver,
kidney,brain,andlung,areexposedtothedrugin
thefirstfewminutesfollowingabsorption(initial
phaseofdrugdistribution).Lessrapidlyperfused
tissues(muscleandskin)andpoorlyperfused
tissues(boneandfat)areexposedtothedrugas
thedrugreachesitsfinaldistributionpatternover
aperiodofhours.

Bloodbrainbarrier
Placenta

Proteinbinding

reversible(noncovalentbonding)
freedrug+protein<>drugproteincomplex
albumin(bindsacidicdrugs)
alpha1acidglycoprotein(bindsbasicdrugs)
lipoproteins

FactorsDeterminingDrugDistribution

FactorsDeterminingDrugDistribution

2. Bindingofdrugtoplasmaprotein

3. Specializeddistributionbarriers

Onlyfreedrugcandiffusetothesiteofaction.
Pharmacologicactivitydependsonfreedrug
concentrationinplasmaforveryhighlybound
drugs.
Reservoireffectmayprolongboththedurationofdrug
actionandhalflife.
Theremaybeexcessfreedrugpresentif
hypoalbuminemiaoccursandresultingtoxicity;
importantonlyforhighlybounddrugs,mayrequire
dosingadjustment.

TheBloodBrainBarrier

Bloodbrainbarrier(BBB)
Nointercellularporesbetweenbraincapillary
endothelialmembranesduetothepresenceoftight
junctionsbetweencells
Effects severelimitationonmovementofionizedor
highlypolarspecies;thesesubstancescannoteasily
penetratetheBBB.
Fordrugstogainaccesstothebrainfromthecapillaries,
drugsmustdiffuseacrosscells(lipidsoluble,nonionized form)
orbeactivelytransportedbyacarrier.

FactorsDeterminingDrugDistribution
3. Specializeddistributionbarriers
PlacentalBarrier
Drugscrossplacentabydiffusion;lipidsoluble,
nonionized drugspenetratemostrapidly.
Usually, placentaltransferofdrugsisrelativelyslow,
withtheequilibrationtimebetweenmaternalblood
andfetaltissuesestimatedatabout15minutesfor
somedrugsandalmostanhourforotherdrugs.

FactorsDeterminingDrugDistribution

LinkageofFetalandMaternal
BloodSuppliesviathePlacenta

3. Specializeddistributionbarriers
PlacentalBarrier
Virtuallyeverydrugusedfortherapeuticpurposescan
anddoescrosstheplacenta;effectively,norealbarrier
exists.Inaddition,manyillicitdrugsandothertoxic
substancesabsorbedbythemotherwillgainexposure
tothefetus.Drugsareclassifiedonascale(A,B,C,D,
X)forsafetyforuseinpregnancybasedontheirability
toharmthefetus.

DevelopmentofPlacenta

PharmacokineticFactors
AffectingDistribution
Competitionforproteinbindingsites
Occasionallysignificant

AlterationofextracellularpH
Usefulincasesofoverdose,poisoning,etc.
Canalkalinizetheurinetoexcreteacidicdrugs

ClinicalRelevanceDistribution
ClinicalSignificance
Veryrelevantinyoursickestpatients
Bloodflowisthedeterminanthere,soalways
considerdistributiondisturbancesinthe
patientwithcardiovasculardisease,vessel
disease,perfusiondisorders
Rememberbarriers

Metabolism
Conversionofarelativelylipidsolubleparent
drugmoleculetoamuchmorepolar,water
solubledrugmetabolitewhichcanbereadily
excreted.
Themorelipidsolubleparentformofthedrugis
noteasilyeliminatedbythebody'sexcretory
mechanisms(renalandbiliaryexcretion).
Drugmetabolismproducesapolar,watersoluble
substancewhichismoreeasilyexcretedfromthe
body.
Thereisindividualvariationinmetabolism
pharmacogenetics.

MetabolismPurposes
Detoxification(defense)mechanism
Chemicalconversionofatoxicsubstancetoaless
toxicmetaboliteforterminationofdrugaction
Chemicalconversionofapharmacologicallyactive
substancetoaninactivemetabolite

SitesforDrugMetabolism
Liver smooth
endoplasmicreticulum
inhepatocytescontain
manydrugmetabolizing
enzymes;someenzymes
arefoundincytosol.
Gutwallandmucosal
surface
Plasma
CYP450