DETOXICATION ROLE OF THE PLACENTA: EFFECT OF EFFLUX TRANSPORTERS AND BIOTRANSFORMATION ENZYMES František Štaud Katedra farmakologie a toxikologie Univerzita.

Prezentace na téma: "DETOXICATION ROLE OF THE PLACENTA: EFFECT OF EFFLUX TRANSPORTERS AND BIOTRANSFORMATION ENZYMES František Štaud Katedra farmakologie a toxikologie Univerzita."— Transkript prezentace:

1 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

2 Placenta EFFLUX TRANSPORTERS ENZYMES ?

3 Efflux transporters and enzymes of the placenta Several ABC transporters have been localized in placenta: MDR1, BCRP, MRPs Protection of fetus against xenobiotics from mother.

4 Efflux transporters and enzymes of the placenta – expression of P-glycoprotein Novotna M, et al. Reprod Tox, 2004 RT-PCR Western blotting

5 Efflux transporters and enzymes of 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).

6 Efflux transporters and enzymes of the placenta – expression of 11  -HSD2 Staud F, et al. Placenta, 2005 RT-PCR Western blotting

7 Dual perfusion of the rat placenta Conversion capacity M>F clearance F>M clearance

8 Placenta PK analysis of efflux transporter activity (in placenta) Maternal Circulation Fetal Circulation Passive clearance (Cl pd ) Capacity limited clearance (Cl efflux ) Total clearance (Cl T ) M>F transportF>M transport ABC F > MM > F

9 Effect of P-gp on placental transport of Rhodamine 123 Pavek P, Staud F, et al. J Pharmacol Exp Ther, 2003

10 Pgp and BCRP in HRP-1 cell line BCRP mdr1a mdr1b

11 Effect of BCRP on transplacental PK of cimetidine 8.7116.7Km 2.477.14Vmax 0.042 CLpd inhibitorcontrolF>M 0.0280.77Km 0.000570.013Vmax 0.0430.041CLpd inhibitorcontrol M>F control inhibitor control inhibitor ~ 0.042 ml/min

12 Effect of BCRP on fetomaternal efflux of cimetidine Cimetidine (100nM) present in both circulations – fetal perfusate recirculated Cimetidine concentration dropped by 13% over 30 min

13 Effect of BCRP/Pgp on transplacental PK ABC

14 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)

15 11  -HSD2 saturability (M>F corticosterone 3-200nM) Staud F, Mazancova K, Miksik I, et al. Placenta, 2005 corticosterone 11-dehydrocorticosterone

16 Conversion of fetal corticosterone Inhibition and saturation Staud F, Mazancova K, Miksik I, et al. Placenta, 2005

17 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.

18 Acknowledgements Current PhD students: Mgr. Martina Čečková Mgr. Antonín Libra Mgr. Lukáš Červený Mgr. Zuzana Vacková Mgr. Leoš Fuksa Mgr. Lenka Cygalová Mgr. Lucie Švecová Mgr. Eva Brčáková Colleagues: RNDr. Jiří Pácha, DrSc MUDr. Stanislav Mičuda, PhD PharmDr. Petr Pávek, PhD Prof. MUDr. Zdeněk Fendrich, CSc Financial support: GAUK FRVŠ Technical assistance: A. Kunová D. Součková