Nebbio

kimetics patcliminatedi
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:
,
,
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Gozeign substance

systaric arewlation otissue stranspocters

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-absoptior
freeerbound
)
eliminantion
phase

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:
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:
o

glzcoproteins cembedded with

membrare bycaccier and
enzynes
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pentic concupoundls
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3
transport high Ecompounds ( ATP transmembrane proteins CABCgradient allowes be absocbed
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);
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:
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secondaiig active transpoct electrochemical but nhightcompounda mrediated by e l e c t ro n i c

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3
aitipoct aurnd sympoetis

Lnodide s in
thyraid than systematic crculation this
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s
]
pacacellulo transpoct sinvesciclos cormpactmant thx to intercellubore
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:
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,
,
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"
by amanging their shrape

cnangzexpenditureabsocption
the
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,
inioires
endogenonus compounds Egruetoses

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,
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og by
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,
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,
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contraz o
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:
,
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poro probelem abssoeption

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o

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o
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o
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Buoderom pH Dorman mambrane veiy

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o
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o

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theraphartic drugs bypass liver isublingual adiministrations
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:
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strong acids lpkaszs sloniaed and

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{ =5-113 isrized
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transferos
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principle subjected
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:
to
;
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passage acrosshiver
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:
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is
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us
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of
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:
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,
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bind to proten colliers ( protens revesible L Fweak wsequilibriim between free ardl boundl
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:
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&i
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!
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,
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o
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bind buas Coa

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,
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aze

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show blood
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l
,
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gr

pastituel fatioophilic substances Lbarbiturates retamine avermectinis physicanl tredistribition

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o

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o
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o

biotransformation reastive matabalites Lbirdl BIsO ar metallothoreln bound metarls inliver

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)
xerobiotics
keyfactor dangerous for livingazanisms found in
plant bc protect thmselves
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s
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o hecbiroces
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synthetize and climinate endogenovs compoords

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us
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termination
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d
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g severall g iptake ecertain
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t

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kidrenz brain musche bore taltow
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,
,
,
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colroous hair mails hoves dlack tis ues
;
,
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kinetics
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.
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XME substrate
specificity tne always specific enzyme for each xemabiotic
:
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rate at wtich ou substrate bixtransfaims deperds on
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similaritiesinaIobutors
families Imoce than byfrabic
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subfamilies cmoze than sat in an identifed by letter onlye invenobietic

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methigiantines
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:
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3 human
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uo quiarititative differences innaturesin humans ard anaimals in
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humran acomatase CUPLaAz

:
reactiers

nydrovlation
phend
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benzene
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rephealed
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c
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Aflatoxis micotarins re p ox i d e
reactive metabolites abte to form coldent bound with
dangezous proteinsts
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:
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botciprafearacin
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fot
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i ve
desuifiration exchange go
:
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orgabophosphozous combound bankier anticnanestrasic engeri

flawaprotains discoveced in
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drugs
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fenbendazdesexidizedy
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sobstrates panasites belminths

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a
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.
:
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substratey birrds the and release ondized ( alt NAopomptex
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,
,
:
,
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ore same
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in
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t
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ose
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e creactive metabolite that
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.
earalemane( estrogeric mycotoxin bydraxy LHSD Lzearatena
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,
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in
genera mace
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:
by microsomal carboxylesterases inplasmo as psendocholinesterasess andamidase
unmasked pelac esterbound
groups mudving water notecule added to
releasig group
shydroliticreactions uindecules
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itoa different pocts
bound
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involved insetticides
in
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,
)
,
biactivetin g
in
prodrugs cacetylsalihc acid and
salicglic acids
ngdrolester

desulphuration e f bound
pnitrophend
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coupond
3 triphosphate
exidantive
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Ltexic detoxifyed in phaselss
,
cothzo
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always
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:
,
,
,
Impoctant indrieffect and
drug pecsistence
glowromsyl t r a n s fe c a s e ; UGT
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citord exept
s

-
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:
grow sinreauced to
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Mest
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substrate substrate
substrate isselfactivated byto oactive a c oz g a t o n

aa conzogared

sstatzle bound
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ace

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:
,
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ismetallic
methyiiazcury
s

mezcory
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BBB)
contains different growps LOH

.-SH
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GLUOURONIDATION sP abundant vridine CUDPGN Dglecose i n cells and rapidly resynthetizedinever a
ratelimiting stept

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:
+UTP.
.
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UOPGA
gercoconidle
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-gewaororide
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5-

gewwöcoräde
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in
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ifdrfferences ofspacies

3
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SULPHATION
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h
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"s
,
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e phosphon
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cytosdic enzyme formetion

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.
cats no able to
conjugeted withgenaozonidation a lot
g substratesciminated with this process

imore
susceptible todrugs lavomatios

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from reactive
:
bc it
not
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sportaneously lonelyi low rare

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,
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Agent with electrophilic oe ncleophilic molecntes tasi ( (

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G5+H
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in

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Gs

,
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osditferente
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.
elemimatled
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desindh
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5-conz}
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less of geotarnigh rawdicaah

:
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e

aacttapatorn afraigsthlina ranalisant

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o

soiy

.
N Endogeros conjugating agent acetyl com
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:
N ( indegs in cytosos results in imparred conjogation avoid prevongued therapiess
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at1zilack
,
;
conjugation substrates ace
arylamines camine on alomatic
graipi

tnd acetylated substrate tave GALCoASH

:
)
Metylatun Endogeros conjugating enzym :
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aderosylmethonine
:
,
+L-methionie,
flethigstransfezases LMT cytosohic and merosomal Etisswen
s
)
Endogenous substrates catrecolanine histamine
:
,
sore
polac erolative moecues isome eliminated
case more cases viethe
veinailg system

quantitative or
qualitative differences
the
lothre
enzyme maybe absent oxthere is eo
prevdogene resulting in the
encoding foe a non
functuoral prokein o
gene isexpressed
with UGT and
but structure natrorm
TAQ
(

1A6
cats
3
Loenzyme ace
expressedi functioning but ace re g u l a y expressed
at a different extend

Pgs prevalences gewcoconidation us sulpnatation sifadminister pbenal aloh

glatoride decilateinw rize

cats
defects some
genes 2
1ipsendogeres not fonctionings OGTIAG and UGTeAQsproten not wockig
sne
general deficieny gewcoronidation (of acomatic sobstrate
,
in

.
in
:
:
s0fams
.
mostly
All glueeroridation isogames involved in
biotransformation of
substrates sbilirobinth
endogenows groid hamores cocticosteroids senval
,
,
,
stewaids mommoness ace
regulalig expressed and
functuoning
A let contain their ideculae structure
Idrugs in acomatic
ringsATTENTION
!
sedative

The half life o drys Laspirin propojolêsthetiçparacetameticaeprojenidant contained in

diezeparn ace
il

much
longer in cats than
dogs
,
-snglammatory,
Tachipirina antipiretic
result in the
gemation o Methernogeobin ciletHg for g exidized AbltzeBono abletocatgh
,
i

intotissues stethal
hyjdtrolisis s

paracetand paminophend dogs will no accumulete

W
:
anscerroscitatabe az
lecking
-acetyleteon
ping
pong
cats lack gewaolomidaton
sno longer able to botransform
-
:
.
p enters in sistemic
cycle boo fhetlts
-ammnoßhend
Epactialylack gwalt pooc expression
Q UGT

Difficult patients be
ofthe diet caacninessdematic compoinds in plants Hyenas brench in comeor
-ancestral
.
N is not efficient
bo threy NATs and
is defective ldonit know
lack
express only MATasglyiination

wng
-acetilation
subcellutal gractuoration to cathalitic
study enzimes
:
centrifugation ghomogenate at loo
g 802
15-20 min toisdate the
fost fraction
-mitochondrial
cent
upper layer mitochondrial
graction osodog
3
cytosolic fracton CSER
)
forgomin
tower
lazer made
og microsaric
greatuon
omicrosonnes mantaired at BoC and used foc inwitco studies
us
bost P aind flawin manooxigerase
4so
Ps in
primaly calture the yield isminimal bo gthe t
blotransformathve enzymes out efthetotal
is low on the
contrang of microsoms
.of
:
,
Phase Ill cexpocti metabdites ne longer hipaphilic
:
Pre metabdism gdrys pass metabdlism

?first
-systenic
limite mayor
exsiensive
Reaction
argan before drug reaches circulations skin nasal throats bronchial tree Centericflora smicrobiate1 istomach intestine
the thre and atT LERY
in
systemic

,
,
,
,
first wwhen there is
pass metabdlism Bimportant an ocal
exposure in case
of paison

ontherapentic effect imitation produced metabdites less active

from
a
pramacological pentgwew in bioavailability
so consequence
on effects Hdosage ead justment
simpact

therapeutic

its interided
externd
of ow
druz oe substance to become
completeng avaiaibe to
bidlagical tissue

Brigi study an transfornation before drug

enreling the blood circulation aind if there will be
trough active
prinaiple to peeform thaterapeutic efifect
immunodepressant

uswahbyz not ecal prepataton be the

intensityof pre metalodism istoohigh onlyo mnimal past will remain
after the first pass metabdism cnatural sexual steroids
cychospotine

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p glwsotominater anal salphate
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cralation andwrine oc vio the biliaty
encretion
Xemoblatics ace excreated intralorized folm polal ,
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faecal rontes Irvelves
drugs not leave the body
through facces
:
esqlso palt excreted we bie

Respiratory roul foc certain

drugs gases and polsons
:
,
cutaneous rate minoe excretion
patway
:
nwer

Billany excretion bilerasng

duct iriestine centeric tract ofbactecial binding between embiatic
enzymes shydrolases
.
and solphatases breaks
(
rich er thee wofandoes

bgeeconidases
:
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daübter swoaed
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proing
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agoiti
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drug othe pecsistance othetoxicitzy of peisons
conjugated comepounds the extent
of reabsocbatin
depends or tore
lipophilicitzy of the released
corepond
L
Ex Bexamethasone LDER cocticestecoid

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with 2 polac less absocbeds
equipped Bhydroxyderinates
3

6 cmice
:
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,
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,
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excreated vio the

circulation
systemic

Drug difficult to measure the persistence

g peison hin
posologyiinpredictabes

Renal excretion 6
dro displey low lipid sdubility
:
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georrecnwrs nndlved in renal excretion
:
kidney proxinal tobale loop of Here distal tubule ts collecting
duct surinaty bladeer
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,
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passage o compound displayng RW LGGO Das
protens ace spaiced
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ractivity grenal filter -
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Drugbenegitpenicillins ampicillin Lanti diretics aspirins (phersobabital
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pection g vrisay tubules in
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,
Factors
affecting blotransformation
Modulatingfactors can be differentaccodingto species, bread, subpopulation (dueto polymorphisms), diet, physlo-pathological conditions
(pregnancy, age,gender

species related differences in DME

CYP1A:well expressed in liver and cattle;involved

of horses in the metabolism and blotransformation of large planat molecule
The rate
of in vitro metabolism
of selected substrates
(study,2003) ethoxyresorufin model substrate for CYP1A1
->

same substrate cam be metabolized at

differentrates accordingto different
Cyp contribution

different cup expression

Affatoxin metabolites aze extremelytoxic and M1 expressed milk - problem for human safety
in
dairy
The eS fold higher production of AfM1 in cattle
hepatocytes us rat
hepatocytes cotelates well with the much higher expression of CYPHA in bovine species

Albendazde (ABZ) antibielmintic compounds medicine millions

retezinaily
in ->

2 kind
of exidation who - they of
the
production of plus enantioner (the phamacologically active metabolite) is
larger in sheep than in cattle

CYP
↳ if moce in bovine,lager amount of inactivemetabolites (increase the dosagel
CYP1A
Futher step:another oxidation - sulfore dezirates (sosal

Monensine:lomphote(compounds freddotic:improve growth

able to
bring wasintocell performances or other zootechnical pazameters

drog:regulates the number of coccidio (intestine patasites

Overentrycause problems for heart, muscles, CNS

large molecule with a

high moleculat CYP3A
weight, blotransformed by metabolites
production of hydroxylated
resultingin the (amostwid of pharmaco-toxicological achon
↳> reduce the amount
of unmetabolized menensin
2St.

For the same nid of cytochrome Peso horsee sene setteeriche lesser extent, compared to pis, chicks, ate"and rats
↓
Highest metabolic rate, highest
toxicity; species
that oxidize morensin ate less sensitive (low
toxicity most efficient metabolizing species (100+

Baccumulate more compounds

AGR:IS involved in CYP induction. CYP1A112 Involved in
botransformation of dioxins and dioxins-like
polychlozinated biphenyl (much expressed in cows than in
sheeps correlated to different
expression of CYP
(EAL
Geratenone:estrogenic mycotoxin with weak affinity for estrogen receptors -> In reductive blotransformation (Hydroxy Stezoid Deidrogenase much more active metabolites are
produced
aisomers pigs produce zlarend (0-OH), moze estrogenic activity -
motelipophitic than ZEA

chickens produce alazend (zEl)

Bread cattle (Polmontese have lower Limousine)

Peso and CYP3A compated to

dogs (Beagtes-perfect dag:Greyhound shows the inabilityofblotransforming preset blacks of CYP2B that
hydroxylase propofal producingnactive metabolitele adjust
the das

a
waysto study drug metabolizing kill animal - > non-ethic process

studythe kinetics:the decrease of ou model molecule overtime in the plasma level e semilogazitmic plot (antipyrine - model molecole be it has been almost

completely blotransformed by cytocrome Paso

The Steeper the slope, the
higher the oxidative

p450 mediated
ofthe animal is
capacity
Cis a fuction ofbiotransformation capacity).
The blotransformative
capacity is greater

than that
of the presenze
youngsubjects be
of antipyrine in the
circulation means that

it has not
been blotransformed.
Little differences between male and
f.
individua

the oxidative blotransformative capacity is

stimes higher in
female than in male

CYP1A:moze expressed in males ->

REACHING IN SEXUAL MATURITy

Humans:different CYP2D:more expressed

180f0ems in woman Impact ofsexual hoemones
->

↳obe stezoid notmones and

of sex lite affected by pregnancy or
bythe population (genetic polimorfism
↳progesteran

Effects of the desease- acute phase response -> cytokies have or be

negative impact they will lead to o decreased transcription of peso and
conjugated enzymes belongingto gewcozol transferase
↳decreasethe collateral effects related on overdose
drugmetabolizing enzyme efficacy drug accumulation
-> er

-> liver
synthetize G2-acidglycoprotein and amyeoid prolanges the persistence of the drug
-

Antipiral medel:antipirin irretics In suine, Injected with LPS-> aftersh the exydative peso capacity of LPS injected is
bfold lowerthen control animaldiseased animals
human have lower
exydeted capacity
Additional
factors due to exposureto xenoblotics or drugs(cause
different overfunction/inhibition of ME
that cause
impared functioning of the whole system)
enzyme Induction/inhibition, drug-druginteractio
↳>

rot x effetto farmaco

Enzyme induction:Increasingof the overall blotransformation capacity of an organism due to the increated number
of enzymatic molecules; latency:long (days,
weeks); reversibility stow
↳ microscopic change (weight, size and SER proliferation
↳
prolonged exposure to ou substrate (not all inducer
given
mandatoty
disappalt
abilityto act on ou given site rather others is limited
(selectivity for bazbiturates, PAHdioxins and polycycic compounds and high for other compounds
not involve all xenobiotics
metabolicing enzymes (mostly phesel;phase DLenly wars and atss)
II
nucleo bound or XRE
In -> er

·Increase in transcription (Increase of transcripts of RNA)

·stowezing of the degradation of the protein (macrolides and ethand):
false increase in the
rigthe molecules

of induction (polltantwith longhalflife):p,per

be to be active amediumspecificiteine Most common mechanism and posts as
longeers but
dioxin
hydrocazbons of compounds
-

Sdrug] must be constant 50 ableto interact

↳omaximum
↳efficacy garanteed specificity,(preventseizures) With Ach
↳dio sin
Joeepitexy like compound
less inducer

->
veryspecific Diffence:different affinity (affinity, degree of inductions)

-veryspecific
Ricorder!Per un efficacie terapeutica basse aumentare le dosi!

Enzyme inhibition:decreasing of the overall biotransformation capacity of an organism -slower speed/no speed all
at
causing no-production of compounds;latency:short (n, days);reversibility:rapid
the

can be caused afterou single exposure;inhibite can be substrate (not prerequisite condition), the number
of enzymes remain the same/decreased

selectivity:high, no microscopie change changes

involves phase II
enzymes(not UGTS and GTSs)
the
competition withthe same enzyme -> repertic treatmentrequires mote than 1 drug at the same time - prevent interaction.
Moensin (concidiostat):administered to animals vie feed -> liver-blotransformed by CYP3A->0-demetilated Monensin
cropharmacological activity
↳ohigher affinity, km laver cattle,rabbit
Tiamulin or macrolides (substrates of CYBA) -> unetabdized Manensin - - systematic circulation- toxic be
conophor
(caties Ions Nat -

Mechanisms inontments

direct interaction without au metabolic activation:N-substituted midazde

antifungals (Moconazoles and Clotrolmidazole) or Nitric oxide
central fest
Bind the not severe
of CYPP450 with a weak
binding -
four of inhibition
inactive until the presence complex
of a

part of the molecule regularly blotransformed, part perform the

inhibition

direct Interaction with metabolic activation:macrolides (Zitromax, zitromicinal veryused

suicide inhibition
t ->
botransformation process stact (2methyl group linked to nitrogen
Stop
cathalitic side of the enzyme 2. demethilation - bound,
nitrosoalkene(covalent
+2)

not completed
CYP3A
Erythromicine: CYP3A, CYPLB, CYPED 2. +
3- blocked
forever
Chloramphonical:boactivated to react to metabolites, Resolved with e denoto
protein synthesis
that are i reactive that kill the
enzymethat perform the potransformation (CYP2311 In dog,
the intermediate is chloride intermediate tapoproteine the human)
examyl destroyenzyme isoform in

↳
INHIBION OFTHE POISONING APPLE

Outcomes inactive metabolite (901):in case

of induction cause or loss of efficacy

in case
of inhibition increase the
efficacy (maybe toxicity

active metabolite:in case the increase

of induction cause
of the efficacy
in case
of inhibition cause the
loss of efficacy
treatmentwith PB, increase benzodiazepines to obtain the serie effectbe reduce therapeutic effect
If ofthose
If treatment with chorampheriad (becticial descase) +
surgety with titetanne-lazepamprolongued sleeping
3inhibit CYP23 that is Involved in blotransformation of anesthetics
 Brug tramspotters LBT

}
Transmembrane proteins embadded in the
phaspholipial bilayger that act as
efflox proteins take the substrates llimitedl and
pormp
them owt
of motecules

:
facilitarted cacciers active tramspolt
transpoct ...

.
,
,
impose a lirwit to
entryg chemicalsspretection guital egans and getus
basobateral mambrame ccentact with
Main
wasclatures
systemmic crculatior
funetion mammazy glend
chenicals
Jowr the excretion
g
livee
kidrey wmisae membrane sbiliaty excretoor
in

)
,
,
indved and bloed to tissue
in
upteke abseeption trensfer from

,
intestinal epitreliom dobe activityiin ot Ii n eminal ibacciers
entry
and maine istmitingte

:
pait

?
colistricts
hepanocytes BT in basolaterals excretion and reuptake inblood
:
napicalcanalicwis sexcrease inthe bitel
2
foem biliangy
kidriegarnd BBB i excretian andreztake

ather T
soluite carliersc m o
rare
n ficthose
a
s s ptae jamilies coo genesencoding
te rs ergarevi escicte transpocters simple transpocters
mitocondria transpocters transpoctes
for
,
j
:
gradierit
lon

do not require E deshase is nat ow problem

,
rrepataytes llivers
the blood to
OCT
LOeganic Cationic Transpocters Jamilies 1-3, uptake gcorpands with the transfer frem

):
the ocal rauke
impoctant foc drugs administred vio

specfamities MATECmuHidrug and Tom Extrusion Transpocters in liver and

kidrey in
excretion gihernicals drugs
pasons,
roe

,
in

):
,
,
insinusolidal capillaries suptake
a
graps QATP
( Anon Transpoctig poly pe tides several
families expressed ghormones and
drug

;
:
Oegaric
at entecia level

QAT logaric to
Transpocters families
b u
1-2, expressedlbaxateal
eson
pact gproximal kidney in

):
impoctant rale in excretian

ATP binding cassette LABC transpocters -7 families 48 genes transpoctera encoding water t rcharnels on charrels specific ABC
)
,
a n s p o c te rs

:
active
onlgoit the
experse ge smediate transfer against grauchient
ws deshronse is on
problena
thre ABCBS
Psps encoding gene is
:
discowazed Chirase Hamster ceirs which lima with resistance to colchicine
in
Qvaty Calte speciziccel
is a a

3
present in tomoral cell hires crnwtation leading to antrenpression ( Brog resistarncOMEDRS Jdevelep resistancetoo

ultipher
also

)
chamnothera
pentic agent
but also towaid colchicine sbatirer
antinenoplasmatic drugs
can wack with BRES LCUPBA mucoseyolimit the entrence xenobotics sintestimal epithelial
o specific
menteric Batlier
in
conjurctoon
wos
drug substrate
o CUP ardlar
Pgps alreadinz within isbuxtrensformed is excreted
3A
usdrug neither CYP mor
Psp substrate sabsolbed aiid traisfezzech to bleed
3A
ho out excreted
smmoze
lasiny
BBB notpermenable to drug absorption and in these cells 2 different drug transpocters LMRPs and P dce active
catching xenobietics
coming

8B53
:
the blood and teer iruto thie blood
from pumpung again

minimate descase
not active
dwring thre
first glize mercury thragh the placente and able to BBB
s
weer methigh
passes is cress
:
Liwee and
kidney expressad in
biliaty tract and renal twrowlat epithelie
:
placenta and
gonads pump drogs fromthie getal sirculamonto the matelinal ee not efficasions to allverdbiotics
:
sorme thirachor lmnow
cam inioit e
m c site diqfereit
hthe
drugs
a
ore is usad with an
n i inkrain
i r
burding from notmallig
)
supergamilies Antide pressant Floxetine
pacoretine
:
,
b
opiaidsimethadore

uctuonis
Artimicrobial retoconazdeldouble ex y t h ro m i n
itraconatde
,
co
immunosopprassoes
is
Miscellarrews
drugs
substrates

compatition of the same IT due to the administration at t h re same

tire gz aifferent
.
compound that substrate arnd crinsibiter
o
wocks ais aw

Antineophastics DevorwbiinDocetaxel Uincristin Wiriblastimi totoposide Mlitorantrone ActimomianB

:
,
,
,
,
,
natwral
sugrathzetznas
steeelds aldostecone coctisol dexamethasone metrglprednisoore
:
,
,
ohubstrates antimirobia resisterce itraconanzoe Ketocorazae Lantigungals
can caush
Erythomycin
:
,
,
Tetranyzcline deoxycichine Levoghoracin spalllovacin Lanzibacterian
,
,
,
cardiacs resestance
reflect on the heakth
of thre patent sDigoxinBiltiazen Werapariih
:
,
,
immunosuppressicsefficient during transplantation swnotel lover expression can have an
iipact
:
and tacrolinos on
cychospocine
missellareos wemectin canti pacasites used
drug for dogs
:
}
BERP ( Cancer Resistant Protan the ABCG
encoding gere is
breast
2
expressed in
different tissues annd cells also in those
circulating Lenteroliztes etythocytes retiro
bone macow reral twbutes
mammatygeandh
,
,
,
,
,
,
wormann aridl ruminaiits

responsible for the actio excretirigdrugs and andtorns imilk

other xenblotics against manydrugs
gradieri

metabdite
the
gaflatorn Byogenetorin carcinogen
?
They increase their expression during lactations if not basal level

highete gmilk excrethie higher ammount of

aflatorin Msexrered and ABCGZ expression
io
amount
,
the kiretics and
polymelBhisms canteke
plase and impact on
toxicity glines Laatis
-mndives
bretinar expression retiral
1 i e r slosdruz as quiraones ( propectiess upan the exposione hight
impottai wa sbathier
s bdefeative
ach to
thong
phototonic
erit ond rachicals pecimaierz blinderess
brodca reactive -
s
MRP the inndved
encoding gere
is
ABCCs in the
excretion a xe r o b t i c s
;
:
-9,
recognize nectral or
weakly basic
orgaric compand and transpoct prase il compardsiweck as cailiers

monly expressed in tissues that ace involved inexcretion kudreg inapical and lead to
biliang excretion
:
liver : in basolateral paict lincontact with vaschlature raan to sinusoidal
capillatiess
,
us
crcuaaton
systervic oegonies
excretionwia
kialneys
Ricade Se nel circolace santidiabatic
un
famaco son
fegatoscontine a
metzocmin
!
Drogidrug competition to the exretor
sNSALDsdrugs pelsons a n t i compounds inethotrerates
-twmowal
,
,
principles gdrug kinetics (

pk}
All the transit
of a
drug into bodysto explein when focwhich and hov
long a cecteh
drog canbe phacmacoogicany
active
i n the
body

,
Posology defines the cose
gdrug fer a patert
and the thetimes goc
adminiszeing this drug
avoiding side
effects

.
Efficanzi duration and
intensityef drugs
actuor related to L
intarget tissues

]
first pestulate kiretics L LJ overtre
o plasmo drug is
agunction g tissue
drug
"
3
calolate
comata
easyto

principal aim is the

graphical rappresentaten gthe transit through
drug the
body by means gmathe matical mootels
therapeltic
Mimitiswem exffective L seosel s s
Toxic threshold
mden
3
inits
Bioqvailability estimation ga drug reaching the systemic crculation
from an extravasal site unmodified folm smetabolites ace excluded
ibefoce metabdizedl after biooveilability

,
I

=Awwerank
is
expressad as o t
compared to maximum
bioqvailability Awcintravanous

.
intrawenows administraion immadiate pooe drug dissolution involves problems in
releasingthe astive
principle

:
limited
stability ac inactivation o active
principle in on

ocal administraton difficultimpossible cherical chacacteristics

physico

-
action
aferitatic drugtranspocters
first pass effect

bßblocker proprand biovaileibility Limiting factor liver in

:
3-17t,
lidacaiza liver
cAnhestatic
bovailaibility lilmiting factoc is in

us
sulphomamide sulgadimethonne t
biovataibiliity
i so
broblem with repatic metabdism

( the rake arid the extent

greabsoption
Cmax maximum
gthedrg ( function o

uglit3i
:
J
rapresented in plasmno [3 tirme curie Tmanx time Im Which CMAX is reachedi inversely coccelated to Crexx
:
AWE wrater the plasma
LJ curve sellow trepezoid ac
triangle rue
ssoftwace
:aiceo
;
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oa drug elimination i measure thetime ( taken
for plasino [ go drugto declire
bysot

.
-life
TuB3:
h)
drug plot g plasmo CJ
/ time
semilogazitimic smonoexporential equation straight line
s
ins

affecred by distribution blotransformation excretion

":
,
,
in gernly distributedspleasmen ciclinterstitial gluld shol
intracellwlar feviet (284
Main Bracmacokinetic Volume Vglade ( o Likg

,
distribution
pacareters of measure the which will be required to contain
the amount odrg
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:
l
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E
at equal tolJin Blasina sappacentiVds TuzBs
3
,
Vd B ttotal dose administered = B
3
:
ciplasma c at
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Bodzy cleazance Wbody giund wtich is
reversibly cleazed
efdrug per writ
o time
byzwacios elimination process i all
processes by wwhichr drugs ace removed
from
the
body
:
indiperndent fram Udiiversengrenated to
half
-lige
Cltet = B ke B
=wolke
=
3
Meim phaciacokinetics models ke AWE
.ADC
One model
postulate b
body single kiretically homogerous unit
airi e withowtr
-compactment
open
:
-
,
between
drugs istantaneosly and mantared an tire
reachied
2
aq drug plesme other is
.
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,
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s
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and out unidirectional
put
input
c
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Losemilogalitimics linaal with

eslope sdCat Inz
=0,693
:-kelosT-InGC
:
-ke
Ke ke Ti
2
Two compactient model central ore
liwver wngsheatl and
peripheralore lfet intestine muscles ... drog can moreback and
joth tomrantain equilibrium
:
B:
,
,
,
,kidnay,
Brug eriter the ard teare thre
s
body bodzoring
vie ther
centralcorpaltmert
andw and id
zL ace plasme LJ
of either
compaltmen
zKei andl Kak dile the eliminaton rate constants constants centrais pacigeral

akeis the elimination raze constants centrais antsiae

sthre
drug repiding distributes in the
central compactment where an equitibrium is ahirnosz
immediatelyebteined at T CS C
2=0
=DSLWI(
:O,
drug transfec lkejocewrs
othe centrol ?
perigetal asthe elimination
from central compoltment according to
first ocdter lretics

wod commpaitment
steepshope c distribution wite the
paripherel compaitment and the dimination
from the
central
?
-prase
[3
isstoardy states
arog plasme
43 = tissue
drug
lcecliminated
uBphese drogs glowbeck inito central
commpoltment vore
thay
Three perjused
compoltment conerpoctment central and peripheral less tissues
:

interemedtieie
perzused tissues