The4PhasesofPharmacokinetics
PharmacokineticsandPharmacogenomics:
ClinicalImplications
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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
• FirstͲpasseffect(presystemic metabolism)
• Duringtheprocessofdrugabsorptionfromthe
gastrointestinal(GI)tract,therearetwopotential
sitesformetabolismofthedrugtooccur:1)gut
wall,and2)liver.Ifthedrugismetabolized
(chemicallyaltered)asitpassesthrougheitherof
thesesites,itissaidtoundergofirstͲpass
metabolism.Effectively,thedrughasbeen
metabolizedbeforeiteverreachesthesystemic
circulation.
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PhysiologicFactorsAffecting
Absorption
• FirstͲpasseffect(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).
ClinicalRelevance—Absorption
PharmacokineticFactors
AffectingAbsorption
• ElevationofgastricpHbyantacids
– Increasestheabsorbanceofbasicdrugs;
decreasesthatofacidicdrugs
• Laxatives
– IncreaseperistalsisanddecreaseGItransittime
• Drugsthatareconstipatingmayincrease
absorptionofothermeds
• Adsorbents
• DrugsthatdecreaseGIbloodflow
Distribution
• Maychangeoverthelifespan
• Presystemic metabolismisconsideredwhen
drugsaredeveloped.
• Highlyroutedependent
• ViathePOroute,makesurethepatientis
awareofthe“emptystomach”rule,ANDthat
itappliestoantacids,antiͲdiarrheals
• 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<ͲͲͲͲͲͲ>drugͲproteincomplex
• albumin(bindsacidicdrugs)
• alphaͲ1acidglycoprotein(bindsbasicdrugs)
• lipoproteins
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FactorsDeterminingDrugDistribution
FactorsDeterminingDrugDistribution
2. Bindingofdrugtoplasmaprotein
3. Specializeddistributionbarriers
– Onlyfreedrugcandiffusetothesiteofaction.
Pharmacologicactivitydependsonfreedrug
concentrationinplasmaforveryhighlybound
drugs.
• Reservoireffectmayprolongboththedurationofdrug
actionandhalfͲlife.
• Theremaybeexcessfreedrugpresentif
hypoalbuminemiaoccursandresultingtoxicity;
importantonlyforhighlybounddrugs,mayrequire
dosingadjustment.
TheBloodBrainBarrier
– BloodͲbrainbarrier(BBB)
• Nointercellularporesbetweenbraincapillary
endothelialmembranesduetothepresenceoftight
junctionsbetweencells
• Effects– severelimitationonmovementofionizedor
highlypolarspecies;thesesubstancescannoteasily
penetratetheBBB.
– Fordrugstogainaccesstothebrainfromthecapillaries,
drugsmustdiffuseacrosscells(lipidͲsoluble,nonionized form)
orbeactivelytransportedbyacarrier.
FactorsDeterminingDrugDistribution
3. Specializeddistributionbarriers
– PlacentalBarrier
• Drugscrossplacentabydiffusion;lipidͲsoluble,
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.
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DevelopmentofPlacenta
PharmacokineticFactors
AffectingDistribution
• Competitionforproteinbindingsites
– Occasionallysignificant
• AlterationofextracellularpH
– Usefulincasesofoverdose,poisoning,etc.
– Canalkalinizetheurinetoexcreteacidicdrugs
ClinicalRelevance—Distribution
• ClinicalSignificance
• Veryrelevantinyoursickestpatients
• Bloodflowisthedeterminanthere,soalways
considerdistributiondisturbancesinthe
patientwithcardiovasculardisease,vessel
disease,perfusiondisorders
• Rememberbarriers
Metabolism
• ConversionofarelativelylipidͲsolubleparent
drugmoleculetoamuchmorepolar,waterͲ
solubledrugmetabolitewhichcanbereadily
excreted.
• ThemorelipidͲsolubleparentformofthedrugis
noteasilyeliminatedbythebody'sexcretory
mechanisms(renalandbiliaryexcretion).
• Drugmetabolismproducesapolar,waterͲsoluble
substancewhichismoreeasilyexcretedfromthe
body.
• Thereisindividualvariationinmetabolism—
pharmacogenetics.
Metabolism—Purposes
• Detoxification(defense)mechanism
– Chemicalconversionofatoxicsubstancetoaless
toxicmetaboliteforterminationofdrugaction
– Chemicalconversionofapharmacologicallyactive
substancetoaninactivemetabolite
SitesforDrugMetabolism
• LiverͲ smooth
endoplasmicreticulum
inhepatocytescontain
manydrugͲmetabolizing
enzymes;someenzymes
arefoundincytosol.
• Gutwallandmucosal
surface
• Plasma
CYP450
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