non invasive methods of estimating pharmacokinetic parameters2

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    OEO @OYMW@YL ALXKEHW EI

    LWX@AMX@OF ZKMTAMGEN@OLX@GZMTMALXLTW

    Dp

    D/ Xk`cmngkmohtm

    A/Zkmtamgp

    Hlzmtxalox ei zkmtamgl|x`gw

    Ymmfhly` `o`wx`x|xl ei zkmtamgl|x`gmc wg`loglw

    Decc`n|oxm# Vmtmofmc/

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    @OXTEH\GX@EO

    Aewx zkmtamgen`olx`g wx|h`lw `oyecyl xkl almw|tlalox ei

    ht|f geogloxtmx`eow `o zcmwam/ Kevlylt# xkl gecclgx`eo ei

    dceeh `w oex lox`tlcp v`xke|x t`wn moh w|dblgxw xkl zmx`loxw et

    klmcxkp yec|oxlltw xe `ogeoylo`logl moh h`wgeaietx /

    @o mhh`x`eo# xkl w|dblgx> amp dlgeal mzztlklow`yl mde|x xkl

    tlzlmxlh wmazc`of ei dceeh# tlw|cx`of `o m wcev`of ei xkl tmxl ei

    mdwetzx`eo itea xkl fmwxte`oxlwx`omc xtmgx moh# zeww`dcp exklt

    gkmoflw `o zkmtamgen`olx`g zmtmalxltw

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    Xve oeo!`oymw`yl xlgko`}|lw kmyl dllo

    tlgeaalohlh mw mcxltomx`ylw xe dceeh

    wmazc`of# omalcp

    =/ Gecclgx`eo ei wmc`ym

    4/ Gecclgx`eo ei |t`ol

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    GECCLGX@EO ITEA WMC@YM

    Ht|f geogloxmtmx`eow mtl |w|mccp almw|tlh `o a`{lhwmc`ym/

    Xk`w geoxm`o wlgtlx`eow itea zmtex`h# w|damoh|cmt#

    W|dc`of|mc moh a`oet fcmohw/

    Amop ei xkl mhymoxmflw ei almw|t`of ht|fw `o wmc`ymtlcmxl xe xkl oeo`oymw`yl omx|tl ei xkl lmwp gecclgx`eo

    zteglh|tl/

    Iet xkl gecclgx`eo ei wmazclw eo m zmx`lox dmw`w# a`{lh

    vkecl wmc`ym `w xkl eocp ztmgx`gmc mcxltomx`yl/ Xkltlietl# `i xkl almw|tlalox ei m ht|f clylc `o wmc`ym

    `w xe dl ei floltmc gc`o`gmc ymc|l `x v`cc ollh xe dl heol

    eo a`{lh +vkecl) wmc`ym/

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    m! mgx`yl xtmowzetx

    d! zmww`yl xtmowzet/ !x

    g! w`azcl i`cxtmx`eo

    l! h|gx glccw z|azOm xe dceeh

    i! glcc aladtmol

    f! zetlk! `oxtmglcc|cmt

    wzmglw

    `! mg`omt glcc

    ALGKMO@WA EI HT\F XTMOWZETX DLXVLLO ZCMWAM MOH WMC@YM

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    Geazew`x`eo ei wmc`ym

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    Geazmw`x`eo ei wmc`ym

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    Tlcmx`eo dlxvllo xkl geogloxtmx`eow ei weh`|a#zexmww`|a# gkcet`hl# moh d`gmtdeomxl `o xkl wmc`ym mohxkl tmxl ei wmc`ymtp icev

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    Alxkehw Yec|al

    Wz`xx`of :/< ac%a`o

    Gklv`of zmtmii`o vm{# zmtmi`ca# = xe 7 ac%a`o

    t|ddlt dmohw# z`lglw ei Xliceo

    et gklv`of f|a/

    Mg`h claeo htezw et m ilv htezw < xe =: ac%a`o

    ei :/< aec%c g`xt`g mg`h

    ALXKEHW EI WX@A\CMX@EO EI WMC@YM

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    XLGKO@]\LW IET XKL GECCLGX@EO EIWMC@YM

    Htm`o`of alxkeh

    Wz`xx`of alxkeh

    Mdwetdlox alxkeh

    HTM@O@OF ALXKEH

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    Mdwetdlox alxkeh

    Xkl Wmc`ylxxlalxkeh

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    Wmc`ylxxl

    Hloxmc gexxeotecc

    =/

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    IET MG@H@G HT\FW

    IET DMW@G HT\FW

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    Imgxetw `oic|log`of zmww`yl h`ii|w`eo ei mht|f itea dceeh xe wmc`ym

    Tlcmx`of xe ht|f

    =/ Mg`h`g et dmw`g# moh xkl zNm4/ C`z`h!wec|d`c`xp

    Tlcmx`of xe xkl g`tg|cmx`of ht|f clylc `o xkl itll+oeoztexl`o!de|oh) ieta

    =/ Oeoztexl`o!de|oh dceeh clylc

    4/ Hewl moh gclmtmogl ei ht|f

    Tlcmx`of xe wmc`ym

    =/ Wmc ym icev!tmxl

    4/ Wmc`ym Zk

    7/ Wmc`ym d`oh`of ztexl`ow ! |w|mccp a`o`amc

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    Iet xkewl mg`h`g ht|fw v`xk zNm ? ;/< moh xkewl dmw`g

    ht|fw v`xk zNm 3

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    WMC@YMTP GCLMTMOGL

    Mggeth`of xe amww!dmcmogl tlcmx`eowk`zw

    Itea hli`o`x`eo ei gclmtmogl

    Itea mdeyl l}|mx`eow

    Tmxl ei wmc`ymtp wlgtlx`eo 1 ]w / GW

    tmxl ei wmc`ymtp wlgtlx`eo1 GCw / GZ

    Gcw 1 ]w / Gw % Gz

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    Ol|xtmc moh mg`h`g ht|fw

    W`a`cmt kmci c`ylw `o wmc`ym moh zcmwam

    Iet mg`h`g lf2 wmc`gpcmxlw# w|czkmzpt`h`ol moh `xw mglxpcalxmdec`xlw# w|czkmalxkm{mrecl

    Iet ol|xtmc lf2 mcgekec# zklopxe`o# xklezkpcc`ol#

    gmtdmamrlz`ol/

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    Dmwlw

    Aewx mtl wxteof dmwlw v`xk zNm ymc|lw `o l{glww ei ;/:

    Wmc`ym geogloxtmx`eo `w ftlmxlt xkmo zcmwam

    Gw % Gz ei dmw`g wkev `oxtmw|dblgx moh `oxltw|dblgx

    ymt`mx`eo Iet weal dmw`g ht|fw ztegm`oma`hl# h`mrlzma moh

    o`xtmrlzma gkmoflw `o wmc`ymtp geogloxtmx`eo cmf dlk`oh

    gkmoflw `o zcmwam geogloxtmx`eo `w `oh`gmx`eo ei wcev

    xtmowilt dlxvllo zcmwam moh wmc`ym

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    \T@OMTP LGTLX@EO EI HT\FW

    Xkl zkmtamgen`olx`g moh d`ezkmtamgl|x`gmc ztezltx`lw

    ei ht|fw moh ht|f zteh|gxw gmo itl}|loxcp dl wx|h`lh

    itea tmxl ei g|a|cmx`yl l{gtlx`eo ei ht|fw moh

    alxmdec`xlw `o |t`ol/

    Xk`w alxkeh mccevw xe wx|hp n`olx`g wx|h`lw xe dl

    geoh|gxlh dlietl aetl hli`o`x`yl wx|h`lw `oyecy`of xkl

    almw|tlalox ei zcmwam ht|f geogloxtmx`eow

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    GT@XLT@M IET EDXM@O@OF YMC@H\T@OMTP L[GTLX@EO HMXM

    Mae|ox ei |ogkmoflh ht|f l{gtlxlh `o xkl |t`ol +mx clmwx

    =:,)/

    Xkl momcpx`gmc alxkeh a|wx dl wzlg`i`g iet xkl

    |ogkmoflh ht|f> alxmdec`xlw wke|ch oex `oxltiltl/

    Vmxlt!cemh`ofwke|ch dl heol dp xmn`of 8:: ac ei vmxltmixlt imwx`of eylto`fkx# xe zteaexl h`|tlw`w moh lomdcl

    gecclgx`eo ei w|ii`g`lox |t`ol wmazclw/

    Dlietl mha`o`wxtmx`eo ei ht|f# xkl dcmhhlt a|wx dl

    lazx`lh geazclxlcp mixlt = ke|t itea vmxlt!cemh`of moh

    xkl |t`ol wmazcl xmnlo mw dcmon> xkl ht|f wke|ch xklo dl

    mha`o`wxltlh v`xk 4:: ac ei vmxlt moh wke|ch dl

    ieccevlh dp 4:: ac f`ylo mx ke|tcp `oxltymcw iet xkl ol{x 8

    ke|tw/

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    Yec|oxlltw a|wx dl `owxt|gxlh xe geazclxlcp lazxp xkl`t

    dcmhhlt vk`cl gecclgx`of |t`ol wmazclw/

    Itl}|lox wmazc`of wke|ch dl heol `o ethlt xe edxm`o m

    feeh g|tyl/ H|t`of wmazc`of# xkl l{mgx x`al moh yec|al

    ei |t`ol l{gtlxlhwke|ch dl oexlh/

    Mo `oh`y`h|mc gecclgx`eo zlt`eh wke|ch oex l{gllh eol

    d`ecef`g kmci!c`il ei xkl ht|f moh `hlmccp wke|ch dl

    geow`hltmdcp clww/

    \t`ol wmazclw a|wx dl gecclgxlh iet mx clmwx 6 d`ecef`gmc

    kmci!c`ylw `o ethlt xe low|tl gecclgx`eo ei aetl xkmo 00,

    ei l{gtlxlh ht|f/

    Gkmoflw `o |t`ol zK moh |t`ol yec|al amp mcxlt xkl

    |t`omtp l{gtlx`eo tmxl/

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    Hlxlta`omx`eo ei NL itea \t`omtpL{gtlx`eo Hmxm

    XKL I@TWX ETHLT LC@A@OMX@EO TMXL

    GEOWXMOX GMO DL GEAZ\XLH

    ITEA \T@OL HMXM DP XVE

    ALXKEHW

    =/ Tmxl ei l{gtlx`eo alxkeh

    4/ W`fam!a`o|w alxkeh

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    MHYMOXMFLW EI\T@OMTP L[GTLX@EO HMXM

    cmgn ei w|ii`g`loxcp wlow`x`yl momcpx`g xlgko`}|lw xe

    almw|tl geogloxtmx`eo ei ht|fw `o zcmwam

    v`xk mgg|tmgp/ oeo`oymw`yl moh xkltlietl dlxxlt w|dblgx geazc`mogl `w

    mww|tlh/

    clww wlow`x`yl momcpx`g alxkeh `w tl}|`tlh iet hlxlta`o`of

    |t`ol ht|f geogloxtmx`eo Vklo ge|zclh v`xk zcmwam clylc!x`al hmxm# `x gmo mcwe dl

    |wlh xe lwx`amxl tlomc gclmtmogl ei |ogkmoflh ht|f

    mggeth`of xe ieccev`of l}|mx`eo2

    Xexmc mae|ox ei ht|f l{gtlxlh |ogkmoflh G=T 1

    Mtlm |ohlt xkl zcmwam clylc!x`al g|tyl

    @i Yh `w noevo# xexmc wpwxla`g gclmtmogl moh oeotlomc

    gclmtmogl gmo mcwe dl gmcg|cmxlh/

    H ` ` i N i \ `

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    Hlxlta`omx`eo ei NL itea \t`omtpL{gtlx`eo Hmxm=/ Tmxl ei L{gtlx`eo Alxkeh

    Mggeth`of xe i`twx!ethlt h`wzew`x`eo n`olx`gw# [ 1 [: l!NlxW|dwx`x|x`of `x `o mdeyl l}|mx`eo p`lchw

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    Xtmowieta`of Xe Cef Ieta

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    MHYMOXMFLW

    Mo mhymoxmfl`w iet ht|fw kmy`of ceof kmci!c`ylw# |t`olamp dl gecclgxlh iet eocp 7 xe 8 kmci!c`ylw/

    oe ollh xe gecclgx mcc |t`ol wmazclw w`ogl gecclgx`eo ei

    mop xve geowlg|x`yl |t`ol wmazclw p`lch ze`oxw eo xkl

    tmxl zcex itea vk`gk m wxtm`fkx c`ol gmo dl geowxt|gxlh/

    H@WMHYMOXMFL

    M h`wmhymoxmfl ei tmxl ei l{gtlx`eo alxkeh`o lwx`amx`ofNL `w xkmx ic|gx|mx`eow `o xkl tmxl ei ht|f lc`a`omx`eo mtl

    edwltylh xe m k`fk hlftll moh `o aewx `owxmoglw# xkl

    hmxm mtl we wgmxxltlh xkmx mo lwx`amxl ei kmci!c`il `w/

    h`ii`g|cx/

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    W@FAM!A@O\W ALXKEH

    @oxlftmx`eo

    Mw x`al mzztemgklw `oi`o`xp `/l/ mixlt 9 xe 6 kmci!c`ylw# xkl

    ymc|l l!NL dlgealw rlte moh xkltlietl xkl g|a|cmx`yl

    mae|ox l{gtlxlh mx `oi`o`xl x`al [| gmo dl f`ylo dpl}|mx`eo2

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    W|dwx`x|x`of xk`w `o mdeyl l}|mx`eo

    Geoyltx`of xe cef

    H`wmhymoxmfl

    Xexmc |t`ol gecclgx`eo kmw xe dl gmtt`lh e|x |ox`c oe

    |ogkmoflh ht|f gmo dl hlxlgxlh `o xkl |t`ol `/l |zxe 6

    kmci!c`ylw# vk`gk amp dl xlh`e|w iet ht|fw kmy`of ceof x%4/

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    GEOGC\W@EO Iet xkl almw|tlalox ei ht|fw# wmc`ym vmw w|fflwxlh mw

    lmtcp mw xkl =06:&w mw mo mcxltomx`yl alh`|a/ W`ogl

    xklwl plmtw# wmc`ym kmw dllo |wlh iet xkltmzl|x`g mohxe{`gecef`gmc ht|f aeo`xet`of ei m ymt`lxp ei ht|fw/ Xkl

    lmwp oeo`oymw`yl# wxtlww!itll omx|tl ei wmc`ym moh |t`ol

    gecclgx`eo amnlw `x eol ei xkl aewx mgglww`dcl dehp

    ic|`hw xe edxm`o/ Xkl ambet h`wmhymoxmfl ei wmc`ym `w xkmxamop ht|fw mtl tlxm`olh iet m wketxlt zlt`eh ei x`al xkmo

    xklp mtl `o |t`ol/ Olv gecclgx`of hly`glw wke|ch amnl

    zkpw`g`mow aetl geaietxmdcl v`xk |w`of wmc`ym mw mo

    mcxltomx`yl xe dceeh et |t`ol/

    Almw|tlaloxw ei wmc`ym moh |t`ol ht|f geogloxtmx`eow

    v`cc |w|mccp dl ei ymc|l# eocp `i xklp mgg|tmxlcp tliclgx xkl

    zcmwam clylc/# d|x `o i|x|tl tlwlmtgk xkl algkmo`waw dp

    vk`gk ht|fw loxlt xkl wmc`ym moh |t`ol kmyl xe dl

    gcmt`i`lh aetl mhl}|mxlcp/

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    Tliltloglw

    Oeo! `oymw`yl alxkehw ei lwx`amx`of zkmtamgen`olx`g

    zmtmalxltw/ F/F/FTMKMA

    Wmc`ymtp H`mfoewx`gw/ HMY@H X/VEOF

    WMC@YM MW MO MOMCPX@GMC XEEC@O XE[@GECEFP/Nmt`o A/ Kch# D/W/> He|vl hl Delt# Zk/H/> Bmo

    R|`hlam# Zk/H/> Tedltx M/M/ Amlw# Zk/H/