Biophysical Models for Prediction of Activity and …mbermejo/Hawaii.pdfBiophysical Models for...
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Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
1© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Biophysical Models for Prediction of Activity and
ADME Parameters: Application to Quinolone
Antibiotics
Mª del Val Bermejo Sanz, Ph.D.Associate Professor of Pharmaceutics
Depto. Farmacia y Tecnología FarmacéuticaFacultad de Farmacia. Universidad de Valencia
España
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
2© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
OutlineBiophysical absorption models
QSAR methods in drug absorption and activity
Oral absorption prediction in drug development
C1
C2
C3
C4C6
C5C7
N N
O
COOHF
N
CH2
S N
O N
CH30.00
1.82
0.27
0.54
F0 : 0.96
-2.56
0.00
0.81
0.54
C0
*C1 : 0.00
0.54
0.54
0.54
0.54
Time (min)
0 100 200 300 400 500
Conc
entr
atio
n (µ
g/m
L)
0.1
1
10
100
BolusOral
Plasma
Lumen
2
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
3© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Closed Loop Perfusion Technique: Doluisio’s method
Cannula
Stopcock
Syringe
Gut
SamplesDrug in SOLUTION•Bile duct closed•Water reabsorption measurement
Absorption rate coefficient:
0cka tA A e− ⋅= ⋅
2a
effk RP ⋅
=
Permeability values
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
4© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Closed Loop Perfusion Technique: Doluisio’s methodAbsorption rate constant:
0cka tA A e− ⋅= ⋅
2a
effk RP ⋅
=
Permeability values
5 10 15 20 25 300.15
0.20
0.25
0.30
0.35
0.40
Time (min-1)
Con
cent
ratio
n(µ
g/m
L)
3
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
5© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Biophysical Absorption Models: Plá-Delfina and Moreno
ka1
membrane
ka
Aqueous layer
lumen
Plasma
ka2aqueous pathway
ka
lipophilicity
da
a
PCCkp
PBPkmKa
+⋅+
+⋅=
Small Intestine Colon
membrane
ka
Aqueous layer
lumen
Plasma
Lipophilicity
ka
a
a
PBPkmKa
+⋅=
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
6© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
n-Octanol Partition coeffcient
0.01 0.1 1 10 100 1000 10000
Abso
rptio
n ra
te c
oeffi
ecie
nt h
-1
0
2
4
6
8
10
12Carbamates
Chromatographic constants
0.1 1 10 100
Abs
orpt
ion
rate
coe
ffici
ent h
-1
0
1
2
3
4
5Phenylalkylamines
n-Octanol Partition Coefficient
0.1 1 10 100 1000 10000 100000
Abs
orpt
ion
rate
coe
ffici
ent h
-1
0
2
4
6
8
10
Ring-Anilines
Chromatographic constant
0.1 1 10
Abs
orpt
ion
rate
coe
ffici
ent h
-1
0
1
2
3
4
5Sulfonamides MW>250 Da
Small intestine
4
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
7© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
HPLC, Capacity factor K'
0.1 1 10 100
Abso
rptio
n ra
te c
oeffi
cien
t h-1
0.50.6
56
1
Distribution coefficient
1 10 100 1000 10000
Abso
rptio
n ra
te c
oeffi
cien
t h-1
0
1
2
3
4
5
Colon
Ring-AnilinesPhenyl-alkyl acids
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
8© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
10 100 1000 10000
1
Distribution Coefficient, DpH:3.00
Gast
ric
abso
rpti
onra
teco
nsta
nt, h
-1
2
0,5
(CH2)n
n=1-7
COOH
Biophysical Absorption Models: Plá-Delfina and Moreno
5
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
9© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Lumenaqueouslayer
MembraneGlycocalyxPhospholipids
Plasma ka
P
f
d
a PEPCk
1 ⋅+⋅=
Gastric mucosa
Biophysical Absorption Models: Plá-Delfina and Moreno
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
10© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Na TAUROCHOLATE: INTERPRETATION OF ITS ULCEROGENIC EFFECT.
Distribution Coefficient (n-Octanol)10 100 1000 10000G
astr
ic a
bsor
ptio
n co
nsta
nt h
-1
1
kako
Lumen aqueouslayer
MembraneGlycocalyx
Plasma
Lumen aqueouslayer
MembraneGlycocalyxPhospholipids
Plasma
6
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
11© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Biophysical Absorption Models: Summary
ka1
ka2
membrane
ka
Aqueouslayer
lumen
Plasma
ka
P
da
a
PCCkp
PBPkmKa
+⋅+
+⋅=
Small Intestine
membrane
ka
Aqueouslayer
lumen
Plasma
P
ka
a
a
PBPkmKa
+⋅=
Colon
Membrane
PlasmaLumen aqueous layer
GlycocalyxPhospholipids
Stomach
ka
P
f
d
a PEPCk
1 ⋅+⋅=
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
12© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Biophysical Absorption Models: Summary
membrane
ka
Aqueouslayer
lumen
Plasma
P
ka
a
a
PBPkmKa
+⋅=
Colon
Membrane
PlasmaLumen aqueous layer
GlycocalyxPhospholipids
Stomach
ka
P
f
d
a PEPCk
1 ⋅+⋅=
ka
ka1
Pa
akm PKaB P
⋅=+
Small Intestine: MW> 250 Da
membrane
ka
Aqueouslayer
lumen
Plasma
7
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
13© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
F
N
O
COOH
N
NR
F
N
O
COOH
N
NR
R= H, Norfloxacin R= H, Ciprofloxacin
R= CH3 , CH3-(CH2 )n -
n=1-5CENAVISA S.A. Spain
Biophysical Absorption Models: Plá-Delfina and Moreno
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
14© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
0.01 0.1 1 10 100 1000 100000
1
2
3
4
5
6
7
0.01 0.1 1 10 100 1000 100000
1
2
3
4
5
6
7
Norfloxacin Ciprofloxacin
Partition coefficient, PPartition coefficient, P
Abs
orpt
ion
rate
cons
tant
h-1
Abs
orpt
ion
rate
cons
tant
h-1
Biophysical Absorption Models: Plá-Delfina and Moreno
8
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
15© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Kaq (h-1) Kmem (h-1) 7.073 0.195 6.944 0.397 6.923 3.322 6.801 4.070 6.782 4.795 6.667 6.210 6.649 14.813 6.541 15.359 6.524 30.267 6.422 33.761 6.405 79.701 6.309 85.387 6.293 181.075 6.201 233.991 6.186 389.164 6.099 545.016
0.01 0.1 1 10 100 1000 100000.01
0.1
1
10
100
1000
Abs
orpt
ion
rate
cons
tant
h-1
Partition coefficient, P
kaq
kmem
kmemkaqka111 += 1
da d
C PkE MW P
⋅=+ ⋅ ⋅
membrane
K
Aq. layer
lumen
Plasma
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
16© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
F
N
O
COOH
OCF
N
O
O H
N
S
CENAVISA 8804 CENAVISA 8919
Flumequine
QSAR methodologies in drug absorption
OCF
N
O
O H
N
O
9
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
17© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
ITODYS. Université Paris VII. France. Prof. Christiane Mercier
n-Octanol Partition Coefficient
1x10-3 10x10-3 100x10-3 1x100 10x100 100x100 1x103 10x103 100x103 1x106
Pef
f (c
m/s
)
0.00
5.00e-5
1.00e-4
1.50e-4
2.00e-4
Flumequine
CNV 8804CNV 8919
Norfloxacin derivatives
Ciprofloxacin derivatives
QSAR methodologies in drug absorption
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
18© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
CH3-COOH
CH3-CH2-CH2-CH3
CH3-CH-CH3
CH3
1
2
3
FO-A1-B11-C1
A2 B12Traze
Vector A1 B11 C1B12
0 1 0 0 0
A2
1 0 1 0 1
1 0 1 1 0
Vizet P. PATQSAR©. Version 2.55. 1997
ITODYS. Université Paris VII: Vizet P. PATQSAR©. Version 2.55. 1997
QSAR methodologies in drug absorption
10
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
19© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
000000.02157140.8154290.837NEW001
00010-0.02278570.8747860.852NEW004
000100.001214290.8747860.876NEW003
001111.39E-160.0920.092NEW002
31011-0.01787210.8018720.784BER016
31011-0.02187210.8018720.78BER015
31011-0.02087210.8018720.781BER014
31011-0.04687210.8018720.755BER013
210110.01960370.6613960.681BER012
110110.02607950.5209210.547BER011
010110.02555530.3804450.406BER010
000110.0578214-0.259821-0.202BER009
310010.0354850.7425150.778BER008
310010.0344850.7425150.777BER007
310010.0124850.7425150.755BER006
310010.005485020.7425150.748BER005
210010.007960830.6020390.61BER004
11001-0.02256340.4615630.439BER003
01001-0.03708760.3210880.284BER002
00001-0.0578214-0.319179-0.377BER001
EQ(V6;V7;V8)V5V4V3V2Log Ka diff
Log Ka calc
Log Ka expCompounds
Topological matrixDependent variable
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
20© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
C1
C2
C3
C4C6
C5C7
N N
O
COOHF
N
CH2
S N
O N
CH30.35
0.64
0.140.140.00
0.00 0.00 0.14
F0 : 0.82
-1.13
0.00
0.00
0.06
C0
C1
C2
C3
C4C6
C5C7
N N
O
COOHF
N
CH2
S N
O N
CH30.00
1.82
0.27
0.54
F0 : 0.96
-2.56
0.00
0.81
0.54
C0
*C1 : 0.00
0.54
0.54
0.54
0.54
Lipophilicity-structure correlation
QSAR methodologies in drug absorption
Absorption-structure correlation
Log P
Log ka
11
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
21© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
C1
C2
C3
C4
C5
C6
C7Fo : 1.03
0.00
CH2
N
F
NN
OCOOH
-0.28 -0.28
-0.28
-0.28
0.00 -0.28
0.56
C1
C2
C3
C4
C5
C6
C7Fo : 0.33
0.00
CH2
N
F
NN
OCOOH
-0.28
-0.28
-0.28
-0.28
-0.28
0.28
0.00
Structure- antibacterial activity correlation
QSAR methodologies in drug absorption
E.Coli
Staph.
Log 1/CMI
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
22© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Topoisomerase
Quinolone
12
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
23© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Predicted Log Ka-0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0
Exp
erim
enta
l Log
Ka
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
R2=0.99
Predicted Log P-2 -1 0 1 2 3 4
Exp
erim
enta
l Log
P
-2
-1
0
1
2
3
4
R2=0.997
Predicted Log 1/Mic E. Coli-1.0 -0.5 0.0 0.5 1.0 1.5 2.0
Expe
rimen
tal L
og 1
/Mic
E. C
oli
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
R2=0.96
Predicted Log 1/Mic Staph.-1.0 -0.5 0.0 0.5 1.0
Exp
erim
enta
l Log
1/M
ic S
taph
.-1.4-1.2-1.0-0.8-0.6-0.4-0.20.00.20.40.60.8
R2=0.95
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
24© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
1. Lipophilicity is the main factor governing quinolone absorption.
2. The absorption-partition relationship has a good predictive performance of intestinal permeability.
3. The antibacterial activity is decreased by the N’ alkyl chain which hinders the access to the bacterial topoisomerase or drug binding to DNA.
13
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
25© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
F
N
O
COOH
N
NR
F
N
O
COOH
N
NR
R= H, Norfloxacin
R= H, Ciprofloxacin
R= CH3 , CH3-(CH2 )n - n=1-5
Homologous CompoundsCENAVISA S.A. Spain
N
F
NN
CH3
R
COOHO
CNV 97104-(CH2)3-CH3
CNV 97103-(CH2)2-CH3
CNV 97102-CH2-CH3
CNV 97101-CH3
CNV 97100H
NameR
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
26© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
n-Octanol Partition coefficient10-2 10-1 100 101 102 103 104 105
P eff
(cm
/s)
0.0
5.0e-5
1.0e-4
1.5e-4
CNV9710X derivatives
CNV97100
CNV97103
CNV97104
CNV97102
CNV97101
14
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
27© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
n-Octanol Partition coefficient10-2 10-1 100 101 102 103 104 105
P eff
(cm
/s)
0.0
5.0e-5
1.0e-4
1.5e-4
CNV9710X derivatives
CNV97100
CNV97103
CNV97104
CNV97102
CNV97101
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
28© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
0
5e-6
1e-5
2e-5
2e-5
3e-5
3e-5
500 50
5 0.5
0.05
DuodenumJejunumIleumColonWhole Intest.
Per
mea
bilit
y cm
/s
CNV97100 conc. µg/mL
P-gp levels
15
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
29© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
0.0
5.0e-6
1.0e-5
1.5e-5
2.0e-5
2.5e-5
3.0e-5
3.5e-5
500 50
5 0.5
0.05
DuodenumJejunumIleumColonWhole Intest.
Per
mea
bilit
y cm
/s
CNV97100 conc. µg/mL
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
30© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
0.0
5.0e-6
1.0e-5
1.5e-5
2.0e-5
2.5e-5
3.0e-5
3.5e-5
500 50
5 0.5
0.05
D J IleumWhole Intest.
Per
mea
bilit
y cm
/s
CNV97100 conc. µg/mL
16
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
31© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
0.0
5.0e-6
1.0e-5
1.5e-5
2.0e-5
2.5e-5
3.0e-5
3.5e-5
500 50
5 0.5
0.05 D
JIleum
CWhole Intest.
+Verapamil
Per
mea
bilit
y cm
/s
CNV97100 conc. µg/mL
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
32© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Model assumptions
Pdiff unchanged along GI tract.Efflux system Km value (affinity) is unchanged along GI tract.Vm= f(expression level).
Ileum
17
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
33© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
max
max
Whole intestine2 2( )
Ileum2 2( )
diffm
d
a
a
i f
a
fb
b b m
CdC P Cdt K C
CdC P Cd
Vt KR C
VR
R
R−
−
⋅= − ⋅ ⋅ + ⋅+
⋅= − ⋅ ⋅ + ⋅+
Time (min)0 5 10 15 20 25 30 35
Con
cent
ratio
n (µ
g/m
l)
0.01
0.1
1
10
100
1000
3.06·10 - 4 (1.76·10 - 4)Vm (nmol·s-1·cm-2)Whole intestine
15.94 (8.25)Km (µM)
3.94·10 - 4 (2.06·10 - 4)Vm (nmol·s-1·cm-2)ileum
3.07·10 - 5 (0.20·10 - 5)Pdiff(cm·s-1)
In situ studyValue (SD)
Parameter
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
34© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
3. CNV97100 shows a saturable efflux process verapamil sensitive.
4. The quinolone effective permeability is lower in rat ileum due to the higher P-glycoprotein expression level.
18
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
35© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
)()( hg EEFaF −⋅−⋅= 11Eg= gut first-pass effects
Eh= liver first-pass effects
Oral absorption prediction in drug development“Bioavailability prediction in drug development: fluoroquinolones. CICYT
(SAF 96-1710)” Director. Prof. Plá-Delfina
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
36© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
)()( hg EEFaF −⋅−⋅= 11
Oral absorption prediction in drug development
1 ka TaF e− ⋅= −
)2(1
ef resf Ta
PRF e
− ⋅= −
( 2 )1
r
bs
es
aTT
aF e− ⋅
= −
(2 ) 1 nAaF e− ⋅= −
19
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
37© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
jugularVein
Blood Samples
Administration(I.V.)
Cannula
Oral Administration
Oral absorption prediction in drug development
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
38© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Oral administration
Group A (8-12 rats)
I.V administration
(bolus or perfusion)
Group B (8-12 rats)
Plasma sampling and
Analysis
AUC0∞
calculation
AUC0t + AUCt
∞
(Trapezoidal rule) ( Ct/k)
Oral absorption prediction in drug development
PK Population analysis: Nonmem v.5.0Post-hoc Bayesian ind. parameter estimation
20
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
39© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Time (min)0 100 200 300 400
Nor
floxa
cin
plas
ma
leve
ls (m
g/L)
0.01
0.1
1
10
100Div=2 mgDoral=4 mg
(1)
Time (min)0 100 200 300 400
Cip
roflo
xaci
n pl
asm
a le
vels
(m
g/L)
0.01
0.1
1
10
100DiV=4 mgDoral=4 mg
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
40© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Time (min)0 100 200 300 4004N
'-Pr
opyl
-cip
roflo
xaci
n pl
asm
a le
vels
(mg/
L)
0.01
0.1
1
10
100 DiV=4 mgDoral=4 mg
(3)
Time (min)0 100 200 300 400 500 600
Peflo
xaci
npl
asm
a le
vels
(mg/
L)
0.01
0.1
1
10
100DiV=8 mgDoral=8 mg
(5)
21
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
41© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
ka in situ
0 1 2 3 4 5 6 7 8
F in
viv
o
0.2
0.4
0.6
0.8
1.0
1.2
Norfloxacin
Ciprofloxacin
CNV97100
Pefloxacin
CNV97102
Propil-NorPropil-Cipro
CNV97104
Flumequine
CNV97103
CNV97101
1.041 kaaF e− ⋅= −
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
42© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Predicted F 0.0 0.2 0.4 0.6 0.8 1.0 1.2
Exp
erim
enta
l F
0.0
0.2
0.4
0.6
0.8
1.0
1.2
b[0]=0.022b[1]=0.936r ²=0.927
1.041 kaaF e− ⋅= −
22
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
43© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Cldis=k12·VcR2 = 0.6741
00.20.40.60.8
11.21.41.6
0.01 0.1 1 10 100
Cl=k10·VcR2 = 0.2145
00.10.20.30.40.50.60.70.80.9
1
0.01 0.1 1 10 100
Vc R2 = 0.0505
00.10.20.30.40.50.60.70.80.9
1
0.01 0.1 1 10 100
Vp R2 = 0.0082
00.20.40.60.8
11.21.41.6
0.01 0.1 1 10 100
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
44© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
4. The in situ intestinal permeability is a good predictive parameter of in vivo Fa.
5. The saturable (efflux and absorption) processes observed in situ (and in vitro) had not a significant influence in vivo in rats at the oral doses used.
6. Disposition parameters……………still under modelling
23
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
45© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
ATP
ADP+P
Passivedifussion
Activetransport
Transporter
ATP consumeVm ap; Km
SAz
ATP synthesis
ATPADP+P
ATP
F0F1 complex
Electron transport complexes
ATP levelsKinKout·[ATP]
Kd
SAz
Molecular mechanisms
Model construction
0.0
0.2
0.4
0.6
0.8
1.0
5025
51
0.5 0.03 mM0.3 mM
3 mM
Ka (h-1)
Sarafloxacin Conc Time [min]0 20 40 60
ATP
frac
tion
0.0
0.2
0.4
0.6
0.8
1.0
predictions
Data fitting
[ ] [ ]in out
d ATPk k ATP
dt= − ⋅
[ ] [ ] 0in out
d ATPk k ATP
dt= − ⋅ =
[ ] 1 in outATP k k= → =
[ ][ ]50
1inap in
SAzk k
C SAz
= ⋅ − +
Molecular Biopharmaceutics. 2003 Hawaii Biophysical models-ADME predictions
46© Marival BermejoDepartamento Farmaciay Tecnología Farmacéutica
Acknowledgments
Funds:− Generalitat Valenciana (GV 99-99-1-12)− MEC (SAF 96 1710)
Compounds: Dr. Joan Freixas CENAVISA SA
Isabel GonzálezCarlos Fernández
Vicente CasabóVirginia MerinoAna Ruiz
Ana
Isabel Vicente
Virginia
Carlos