detoxication role of the placenta: effect of efflux transporters and biotransformation enzymes
DESCRIPTION
DETOXICATION ROLE OF THE PLACENTA: EFFECT OF EFFLUX TRANSPORTERS AND BIOTRANSFORMATION ENZYMES. František Štaud Katedra farmakologie a toxikologie Univerzita Karlova v Praze Farmaceutická fakulta v Hradci Králové. Placenta. ?. EFFLUX TRANSPORTERS. ENZYMES. - PowerPoint PPT PresentationTRANSCRIPT
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DETOXICATION ROLE OF THE PLACENTA:
EFFECT OF EFFLUX TRANSPORTERS AND BIOTRANSFORMATION ENZYMES
František ŠtaudKatedra farmakologie a toxikologie
Univerzita Karlova v PrazeFarmaceutická fakulta v Hradci Králové
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Placenta
EFFLUXTRANSPORTERS
ENZYMES?
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Efflux transporters and enzymesof the placenta
Several ABC transporters have been localized in placenta: MDR1, BCRP, MRPs
Protection of fetus against xenobiotics from mother.
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Efflux transporters and enzymesof the placenta – expression of P-glycoprotein
Novotna M, et al. Reprod Tox, 2004
RT-PCR
Western blotting
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Efflux transporters and enzymesof the placenta
Enzymes of phase one (CYP1,2,3 families)phase two (GST, UDP-glucuronosyltransferase, sulphotransferase, N-acetyl transferase).
Clinical significance??
Mainly metabolism of steroid hormones (11-HSD).
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Efflux transporters and enzymesof the placenta – expression of 11-HSD2
Staud F, et al. Placenta, 2005
RT-PCR
Western blotting
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Dual perfusion of the rat placenta
Conversion capacity
100*metaboliteparent
metabolite
M>F clearance
pma
ffvmf wC
QCCl
.
.
F>M clearance
p
ffm w
QERCl
.
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Pla
cen
ta
PK analysis of efflux transporter activity (in placenta)
MaternalCirculation
FetalCirculation
Passive clearance (Clpd)
famamefflux CK
VCl
/
max
Capacity limited clearance (Clefflux)
effluxpdT ClClCl Total clearance (ClT)
mampdTmf CK
VClCl
max
M>F transport
fampdTfm CK
VClCl
max
F>M transport
ABC
F > M
M > F
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Effect of P-gp on placental transport of Rhodamine 123
Pavek P, Staud F, et al. J Pharmacol Exp Ther, 2003
Transplacental transport of Rho123
0
0,1
0,2
0,3
0,4
0,5
M>F F>M
Cle
aran
ce (
ml/
min
)
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Effect of BCRP on transplacental PK of cimetidine
8.7116.7Km
2.47 7.14Vmax
0.0420.042CLpd
inhibitorcontrolF>M
0.028 0.77 Km
0.00057 0.013 Vmax
0.043 0.041CLpd
inhibitorcontrol M>F
M-F clearance
0,000
0,010
0,020
0,030
0,040
0,050
0,060
0,001 0,01 0,1 1 10 100 1000
Maternal cim etidine concentration (uM)
Cle
aran
ce (
ml/m
in/w
)
control
inhibitor
mampdTmf CK
VClCl
max
F-M clearance
0,00
0,10
0,20
0,30
0,40
0,50
0,60
0,70
0,001 0,01 0,1 1 10 100 1000
Fetal cimetidine concentration (uM )
CL
(m
l/m
in/w
)
control
inhibitor
fampdTfm CK
VClCl
max
~ 0.042 ml/min
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Effect of BCRP on fetomaternal efflux of cimetidine
Cimetidine (100nM) present in both circulations – fetal perfusate recirculated
Active efflux of cimetidine from fetal compartment
80
85
90
95
100
0 5 10 15 20 25 30
Time (min)
Con
cent
ratio
n (%
of t
ime
0)
Cimetidine concentration dropped by 13% over 30 min
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Effect of BCRP/Pgp on transplacental PK
ABC
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11-hydroxysteroid dehydrogenase (11-HSD2) in placenta
• Regulates transport of maternal glucocorticoids – conversion to inactive 11-keto form
• cortisol cortison (human)
• corticosterone 11-dehydrocorticosterone (rat)
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11-HSD2 saturability
(M>F corticosterone 3-200nM)
Staud F, Mazancova K, Miksik I, et al. Placenta, 2005
corticosterone
11-dehydrocorticosterone
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Conversion of fetal corticosterone
Inhibition and saturation
Staud F, Mazancova K, Miksik I, et al. Placenta, 2005
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Conclusions
Efflux transporters in the trophoblast can remove substrates from fetus to mother.
Similarly, some enzymes may metabolize molecules in the fetal circulation.
Transporters and enzymes play a key role in detoxication of the fetus.
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Acknowledgements
Current PhD students:Mgr. Martina ČečkováMgr. Antonín LibraMgr. Lukáš ČervenýMgr. Zuzana VackováMgr. Leoš FuksaMgr. Lenka CygalováMgr. Lucie ŠvecováMgr. Eva BrčákováColleagues:RNDr. Jiří Pácha, DrScMUDr. Stanislav Mičuda, PhDPharmDr. Petr Pávek, PhDProf. MUDr. Zdeněk Fendrich, CSc
Financial support:GAUKFRVŠ
Technical assistance:A. KunováD. Součková