distribution and protein binding (kinetics)

8/4/2019 DISTRIBUTION AND PROTEIN BINDING (KINETICS)

1/11

Distribution Is the pnrcess oftrmsporting dnrgar,:tlecules fronr thecentri l c0nrpartntenti4iqr greripher.rlCrlOrfdnnreOt:-Is tbe pn,cess br- r-hicha dmg is c:rrried frrrnrr EstracelluLrr spnce

intrr t l re in test i t ia lsprrce ircross^ th ecapifirn nrenrbrirne

r Intentrtrlrl spi lce rot!:,the tlssue cello- ucr,rssth e cellrrlarnremhranes

3 Biological Fluid Compartment forPharmacokinericConsiderationsr Infirvasal (intravasculer) f luid - i.e.plrsmar Interstitial fluid - brings nutrients anddrtrgs to cells and carries awav waste

prodrrctsr Intracellular {Iuid

Biological Fluidr Is th e selricle bringing tlre dnrg nrolectrle to rndasav fnrm the nrenrbrane

r Ltnrph - is the thin opaleo^cent flrri t l originating rn() rgiros-.and tissrre"-. hirt cin'rrl irter^ throrrglr th el1-urphatic ressels and i.^ fi l tered hv the l i-nrphncrdesr S9hole hl:'od

tr-y*ph

r (bllular (fermred elenrents-)r RBCr VBCr Plateletsr Yaricrus other proteins -

albumin, glrbrrlinsr Estracelltrtar {ltddr Intemtitial fluidr Plsnra

rSemm is obtainedfmm the shole bl.:ndbr remr:rring th esoluble proteinfibrinogenr Intraceltul,rr llrrid

Whole Blood$+

J.i:::-p166;-t;' ---'i+h- F.e.rs 4- - -_: :r]:t


2/11

TotalBodyWeight= 100%Total Bcdr Wrter = 6{Fzi trods

Ilnrr...llul{F!gl4 i Eir.ccllul.. lluid(20 - 257r body w.igh)35- aAi Hy w?i9h1 iJ6

-

30011% 1*

IntrgrhialFlu id l0 L Plasm1.5-, lL

J

Determination of Biological Fluids\FBF - from Vo of aa1- srrbst.rnce rshich isaooelectroh'te rr.ad mises or dissoh-ed io s-eterEL-F - usiug cheur icet incl ic;r tors:r Thiosrrlfater Meonitolr lorrlin

Pl . rsor l r -olr r rne trsing chenr ical indici l tors:! Et i rns bhrer Tlprn redr L;lI-:rlbrrmiur Tett:riodiue Ilrroresceiu

Factors Influenciug Dnrg DistributionPhvsiologic f:rctorsr fliffu sion, fft-drosraticPressure & AbsorptirePressureI flistribution Helf-life, BloodFtos-,and Drug Ilptake br .()rgansr DrugAccumulation

r fliffusionalB:rnisr fli:rmeter & Pemrelbilitrofcel l and capi lhrr nrenrt ineI P:rthophvsiologic conditioos

r Pn'tein trindingr Phr-sicochenrical

factrrrsr Molecrrlar sizer f)egree of

fonizatirrnI Lipid-sater

Partitioo (irelficient

Htdrostetic presuc (fi ttntion)r Rcprscuts the prssuregtadicnt bctsrcco the erterialmd of thc cepilleries mtaingth< tissuc ud ahc soouscepilleric lcaring thc tissucr Thc encriel cqd ofthc

crpillen is ch.Fi(rsized bThtgher presure (8 nm Hg). p,**lalrus forcc plesme enddissolrcd nutrients (eluose,emiao ecids. ritemins) out of lffithe capillerr ud into tissuc Frcas.flrridI Is rsponsible for pcntariouof weter solublc drugs into

sprc6 bctsem mdodrelielcclls ud hmph


3/11

AbsoqptivePressure

Absorptive prs$ ur e (colkridosmotic pressure)r Refers to the lrls-er

pres$ure of th e venousbkltrd compirred sith th eti*sue fluid

r The end of thc venouscepilleries ischirrircterized bt- lorr erpressure, thtrs bl , rodproteins (e.g. albtrm in)pull t issue fluiclcontaining cellul:r r r;r'as eprodtrcts lrack to thecrpilLrries

-r*l'ta

F ,st .iaf -'+.i\ : ,.i'il

\ ; l*

fata

'*-JCardiac Output nnd Concept of Regronal

Blood Florv (tissue perfusion)

Homeostasis[s the beLrnce hetrr-ee n opposing pressures inthe bx>dv with respct to verious functions lnd toth e chemica! comfx]sitious of th e fluids andtissue sH.tp mirint:rin bkrod volume end t trrod p.essure

Rate Limiting Step in DrugDistributiont Di{fueion or pe$neabiliry fiimitedwhen rrd*g fistribution is limitcd b-y thc e'.lon'di{fusion of d*g ircross the memtrr:rne in

the tissuet Pedu,sion or flow. Iimited*'hen I dnrgdiffusee rapidly across the membrane insuch r \ray that blood flov' is the rilte-Iimiring:step in the distribution of drug (..g.,CHF hrrs decreesed (l(), resulting inimp:tired bl rod flow, which may reducerenrrl cle:rrance thr,rugh reducei fittr"tionpressure and blood florr)

Nornral CO rirlues -2.2 -3.5 or {.5L/nr in / n2Regionrd hl.rod fl.rwr f s the rtnrotrnt of

trltrrd delirened trrdifferent organs

r Is an inrlxrrtantfarctor indeternrining theinitial dnrgfistribrrtiirn


4/11

Factors thet determine thc distribuio.,r*/constant of a drug iuto rn org ^nl"/r Blood {lors to t$e org-r-c

r l-*ge blood flos- decreeses the distributioatime

r Yolrrme (size) of tt e organr Le,rge orgirn size or volume increeses thedistribrrtion tirn e

I Accrrurrr let ion oI t l re dnrg in t l re t issrre

Blood FlorvBlood Bors - is en impone.at considemtioo b detcrsrininghow repid end hos much d*g rceches the rer-cpror sitcr Llndcr oormel conditions ligrircd btood flow rret$es rbemusclcr, but durins esercisc mr!- chrnge thc fretrion ofdrugI f fnder nonnal coudidons. ]r lood resen'e s{rr-$ mosrh-inlerge reins rud sinuses of tlre ebdomc' btrt i' crsc ofinitrn- or sr-hen blood is lost constrictiou of lerqe r-cinsredirect blood to needed erersr Accumuletiou of carbon dioside mr$ lowcr tbe pH ofcertlin tissues m.l- elrecr tbe lsr-el of dnrg rcechingthose tissues

W,D*g Accumulation

r Accumulation of drug into tissues isdependentr Blood IIos'r Affinity of the d*g for the tissue

r Deposition or upt:rke of the drug into thetissuer fs controlled by diffusional b..rrrier(capilltry membrane and other tissues)r Is generally reversible

Tissues recei'ing high btood {Iow equitibratequickty with the drrg in the plasma, howercr, rtsteady-stete the d*g mry or may notconcentrate within thc tissueFor rhugs with low tisserffinity

Fordrqgs with hlgh tissueeffinily

Drug concentration in tissueequiliFrrrtes mpidlr. $irhplasne d*g conrrntrrtionrad dec'lines rapidlr rs thcdrug is elisrinered &om thebodr-

tlrug conccntretion in tissueequilibmtes elorrll- $ith ptasmed*g concqrtrrtioo. enddcclines strostv es thc drue isclimineted &om tLe bodr.

Thus, drrrgs tcnd torccumulltc or (-oncentrrte inthe tissue


5/11

For drugs nifh r highitl/u' e fer pe rtition coefficient

l ]nrgs tend tr t accunrrrLrteslr.rs-lr in lipid or irdilx.rse tiso-rrethus, estmction of dnrg r.rtrt ofth e tissrre is *^1; [r.rrr- lratt dnrgrenri r ins f , . rrdan-s (.)re \-e11 ,rngerrn t is. '^tres, r . rng after i t i "depleted in the bl ,r , . 'd

For drugs or rerctil-e,nrefrbolite thrf erecot-rlentlv boundetl tor nt:lcronlfuile

iuirhin the cellIrrerersihle hindingnl i rr r )ccr l r and thus

idrus renra ins f,rr dar-slFII rn trssttes^

First Order Distribution RateConstant & Distribution Half-lifeKd=Q

VR\fhcre:k = 6rst ondcr distdbutionco0strotQ = blood flosr- o thc or.qrnV = r'oltrnre of th e orgenR = retio of dnrgcouccutution in tlre or.gantissuc to drug coocerrtretiouin the blood (r-enous)

I flistribution helf-lifcmersures thc tiore fordnrg distribution or thetime for SCI%distributioat.n = 0'693/klr

I If eech tisstre has th es:rrne abilitr to store tlrednrg, distribtrt ion lrelf-life is gosemed br- bloodflorr end r-olume (size)of the orgen

#vf)d,wg Distribution in 5 Groups of Tissues

at Various Rate of Eqtrilibration

Tinre ( ninutes/hours )

ocll-aaEgtt)E0(,OtOt-

-r'tt0ota

l\hite tkidner')/['ink (edren:rlg lendsl= 957.


6/11

Pathophysiolo gic conditions AlteringPermeability of Cell Membranes

Btrrns - \siU alter tbe rFrTneaFrlurr.-tIrne ff iskin and allorr- d*gF f ; #Fi.:'t - t--]!and Lrcgerm,lecut,." ,o;iff, .frcrrneate ins-ard or tf{ffi, f*i.rr.r--


7/11

Factors Influenciog Drug-ProteinBinding

I [.)nrgr Phr-ticocherni.d pnrpertiesr Totarl concentration

I Pncrteinr rufinitr- bets-een dnrg and prcrteinI Dnrg intenrct ionst Perthoplrr-o^io log ic cc,ndi t jons of the p:t t ient

Functions of Plasma Proteinsr Exert t t'bu{fbr function "(constant

concentrat ion of free d*g can be maintained)because pnrtein-bound d*g can free itsetf inorder to maintain a balance betx'een therelative amounts of bound and unbound drug

r Exert 'a "trznsport functiontt(dngs of losnsolu tr i li qv in sr-a er)

Signilicance of Protein Bindingr Inff uence the dis tribution eguilibium of

drugs, onc equil ibr ium is estebl ishcd, i t isassumcd thet the free, unboundconcenrarion of drug is identical in zllcomPercm crrrs

Characteristics of Protein BindingBinding either to plas-ma pnDteins (inenbinding) and tissue proteins (receptorbinding)Binfing is usually held by weak bonds (vander Waal's and ionic bonds) end is usuallylrut not always reversible such asisoflu roph ate, cyclophosph am idepntSl are primarily bounded to plasmeproterns:

I Albumin for acidic drugsr Alph,r-acidglycoprotein for basic dnrgs


8/11

Characteristics of Protein Bindingt Binding is l imitedr Pmtcin bound drug is usually inactiveuatil frcer llfostlv nonspcific binding cepacity form anv'd*g" r'hoo'.rrer, m *f 'b. lp."ifi .to trece proteins

cenr loplasminsiderophi l l in

r Flemin hemogl,rbin

J

Characteristics of Protein BindingHigher binding provides a depott When plesma lcrels fell, thesc stored drugb(protcin bound drugs) are gradually releasedr Stored drugs hase gener:rtty prolongcdphnqacologic e(Tects thus, -d.!:y-t urineryexcretion and prolong dnrg helf-lifer If d*g storege is extensive encl rapid, thedi"^tr ibut ion i"^ al teredBinding ir altered bv other drugs '.rsa restr ltof drr g c( 'mpet i t ion resul t ing to d*gdisplaceme nt

Pa thophysiologic Conditionsc*n cause alterations (abnormal levels)

of Plrsme Proteinsr t.Tndernutritionriver or kidnev discase cruseftrw cvelsof plasrnNelbumin thus decrerse npnrtein binding sites and increeses rmountoffreed*g resulting in toxicitvr Drug dosege rnust be rcduced

r Acute inllammation tend to increase c,-acidglycopnrtein - increased binding of elkelinedrugs thus decre,rse in free drugr Initial dose requirement m:ry need to lre

increased

Cousequences of Protein Bindiogr Cornpetitive inhibition mry result todisplacernent

r f)isplacement is clinically significant if ad*g is more then $lo/c-X)ahbound toplesrnr proteins e.g., diazoxider One with leso^ ffinityrrill be displaced,resulting in high.r "bo".ntration of freed*gr lWore severc toxic reaction is expected upondisplacement fo r highly protein-bound d*g


9/11

Hypo-c{bomlnen*c Hypec-dbum{nerrilo DecrearadAlpfto-dycoprotcinlncrearedAlpho-gfycoprofein

irrns Dee*ln l,urnorl t{eptroficryn&ome ConcerCcacer l{euroir fniommslion

Cordioc loilrre Psychosir }lyoccrdic{infsc*onlnllommslions Schizophrenio Trqum


10/11

Drug.r nith lon' ti.ssueuffinit.r'

Drugs nith high tis.sueuffinin-

Dru.g cooceotr:rtioo in etis srrc eqrrilibr:rtes repidlr-witlr the plrrsmil dnrgco&centration and thendecliues r.tpidlr- :rs t lredrrr.g s eliurinrrted fronrt lre bodr-

f)nrg coocerrtretroa intissue eqrrilibrrtes slowlrrdth the plasmir dnrgcooceotretion md thendecliues slosr-lr-its he drrrgis eliurineted frour tlrebodr-f)rrrgs tend to :rccusrulirteor concentr'.rte in tlre tissrre

Effect of Protein Bind$g on the YoFor dnrgs that are higbls bounded to p!1ma ptoteins{coatdied i.o plrsmit rsater} - dccrcase VoFor esteosise d*g binding io ttre cells - incre-as. Vo(t..g. cell rolume)For dnrgs that are estensiveh- bounded to both ticEue'and phJot. protein" - Vo is osceptiootlt)' t"tg. ( dueto unusual tissrre binding)r e.g. irnipramine, vincr ist ine

Disptacenrentof dnrgs frtrnr pl:usrne proteins nla\c.tt lse e tr.rtrsierrt incretL\e ir t \t or (Xircitlin - 8o," free, 0.+{ L/kg VDr lbuprrrfen - [7 r frr:e,O-lt] L/[g Vo

$,\"^}fl\I

Effect of Protein Binditg onVDFor Bome d*eS that witl move into theinterstitial fluid but tre unrble to diffuseacro$ the cell membrane into theiatracellular fluids - VD is reduccdWhen no drug bindiog occurs in tissue andpl-a.sma VD will not exceed the realanatomicel volumc because some dnrgs donot obcy binding nrlc e.g., [NH, heparin,lithium

-a;;

t-i tF'tur:r rerrtr-:i :.;s; ft r".rr ir tr.i- a: i>!


11/11

VD Based on the Actuel DrugConcentration Found in the BloodIf the \-p is approd'..lteh- 5 lirers

r drug is cc'o6ncd to tbe circr.rlrtorr r1-s{cm sc,l*lr (ario. \-p murl be*t l,::.rst *"qu;rt rc irlrsrrr.r rolture: iJ; . of bo.lr n-eig{rt }If thc l'p ir bcsscca t}2e Htcrs'

distribution and protein binding (kinetics)

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