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Pharmacokinetics and Pharmacogenomics
Pharmacokinetics and Pharmacogenomics
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