Summary ADMET

Sum ADMET
Mary

Lecture 1 :
Absorption

-


Routes of administration
-
topica 1 :
10cal exposure
circulatory System
:c
System
-
:



-


enter A1 : GIT
GIT
paren ter A1 :
avoiding
-




-




Absorption depends OM
-




physicochemical properties drug
-




Physiological Properties site of absorption
-
Administration environment
-

GIT : stomach
-

Limited absorption

Hydro lytic enzymes
-




-




mucusproducedsurfaceiiningep.itheli al cells
•

GIT : smalt in testine
-

duodenum jejunum and ileum .




-




absorptie in
-

first site metabolisch
bite acids
soiubiiity enhanced
by
-




-

Main cells involved in absorption : en
terocytes
Mechanism s of
drug absorption
-




trans or paraCellular passive diffusion
-
-




-

Active transport
endocytoseis
-




-




passie diffusion
and
-
baiano between
soiubiiity permeability
Fick S first 19W
'
-




DQ
It = D ✗
P ✗ S ✗




Linear process
-




-
Non - saturatie

,•
Facilitated diffusion
-
Michaelis Menten

DA
☒
= -




VIII
-


saturated process
- de
pendant on number of channels or carriers

para Cellular transport
-




tight junction 5
-




-

occludins and Claudia
Claudine
Leak Vs
tight
-


.




↳
depends on tissue
-
smal/
hydrophilic molecules
-

Active transport

primary
:
ATP required to transport against conc gradient
-
.




Secondary :
Movement of ions clown gradient couped with
-




molecules againstgradient

substratespecii ty-efr.lu/:widesubstratespecifity
-


uptake : narrow


Nat / kt ATPase at basoiateralside as
driving Force
-




Nat wat
-1
gklc .

je




µV
nemen
-




""°" """




-0¥ 2kt
basoeterai

Kt (l
-

3 nat




.

ABC ( ATP
binding cassette)
-

transporter
physiological role
-




-
cholesterol and lipid transport
antigen presentation
-




-

mitochondria1 iron homeostaseis
ij

, primary active transport
-




-
Ex porters

In
enterocy.es
-




api (al side :
transport EO lumen
-




-


baso lateral side : transport to bood
-


ABC transporters
associated proteinS CMRPS)
muitidrug resistance
-
-




-
anionic drugs
glutathione. giucuronate.sulfateconjugal.es
-




breast Cancer resistance protein ( BCRP)
-




hydrophobiccationslanions-sulfatedconjugates-p-giy.co
large
-




Pgp)
protein (MDRI /
-




hydrophobic cationic drugs
-

often have aromatic rings and Ntr 4
-


MW >
400 . pka
>
4 .
N t 0 38

SLC ( 5014te Carrier ) transporter
•




Secondary active
-




Physiological role s
-




glucose transport
-




-

ami no acid transport
-
SK example
-
0 AT I

-




Organic anion transporter
-

basoiateral uptake of an NS into tubular ep cells
.




-

in teracts with a lot of drugs
-

OAT 3

-

suipate - and giucuronides-eroidconjugal.es
-

OCTI / 2

-




Organic Cation transporter
-

uni porters

OCT 1 Ii ver OCT 2 :
Kidney
-

:
,




-


OCTN 1 / 2

Cati on and Carriere transporter
Organic
-




-
MATE 1 12

, and
Multi
drug to✗in extrusion transporter
-




-



proton -
Cati on anti Porter
-

OATPS
-



Organic anion transportîng polypeptide
and
uptake of bulky hydro phobic ani ons
-




↳
bilesalts.steroidconjugat.es ,
hormones
Efflux transporters rate of uptake
mag regulatie so
C p 450s
'




are not saturated
-


B( S absorption
-
I :
high 501 .
t
high perm .




I : 10W 501 t
high perm
-

. .




-
☒ :
high 501 . + 10W Perm .




-

IV : 10W SOI .
t 10W Perm .




PAMPA ( parallel artificial membrane per
meabiiity assa )
-




sive diffusion over Micro porosus filter
pas
-




-




high throughput and cheap
-

(en based assays

-
( acoz (human colon adenocarcinooma)
-

MDCK cells ( Carine distal tubular)
-



polarized Mondayer of cells

presence of drug transporters
-




A →
BL BL - A :
passive diffusion
-

=



-

Active transport cel based
MDCK HEK 293 LLC PKI
-

-
. .




-


Cen limes transfected with transporter
-


use of inhibitor for certain transporters

Uptake as
says
-




-


Concentration increasesinsideceus
-

cells then Iysed -
Measure compound
when cells do not form continent
Necessary Mondayer
-




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