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DETOXICATION ROLE OF THE PLACENTA: EFFECT OF EFFLUX TRANSPORTERS AND BIOTRANSFORMATION ENZYMES

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.

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DETOXICATION ROLE OF THE PLACENTA: EFFECT OF EFFLUX TRANSPORTERS AND BIOTRANSFORMATION ENZYMES

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  1. DETOXICATION ROLE OF THEPLACENTA: 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 enzymesof the placenta Several ABC transporters have been localized in placenta: MDR1, BCRP, MRPs Protection of fetus against xenobiotics from mother.

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

  5. 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 (11b-HSD).

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

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

  8. M > F F > M ABC Capacity limited clearance (Clefflux) Total clearance (ClT) M>F transport F>M transport PK analysis of efflux transporter activity(in placenta) Passive clearance (Clpd) Placenta Maternal Circulation Fetal Circulation

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

  10. control inhibitor inhibitor control ~ 0.042 ml/min F>M  control inhibitor  M>F control inhibitor CLpd 0.042 0.042 CLpd 0.041 0.043 Vmax 7.14 2.47 Vmax 0.013 0.00057 Km 16.7 8.71 Km 0.77 0.028 Effect of BCRP on transplacental PK of cimetidine

  11. 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

  12. ABC Effect of BCRP/Pgp on transplacental PK

  13. 11b-hydroxysteroid dehydrogenase (11b-HSD2) in placenta • Regulates transport of maternal glucocorticoids – conversion to inactive 11-keto form • cortisol cortison (human) • corticosterone11-dehydrocorticosterone (rat)

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

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

  16. 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.

  17. Acknowledgements Technical assistance:A. Kunová D. Součková Current PhD students:Mgr. Martina ČečkováMgr. Antonín Libra Mgr. Lukáš ČervenýMgr. Zuzana VackováMgr. Leoš Fuksa Mgr. Lenka CygalováMgr. Lucie Švecová Mgr. Eva Brčáková Colleagues:RNDr. Jiří Pácha, DrSc MUDr. Stanislav Mičuda, PhD PharmDr. Petr Pávek, PhDProf. MUDr. Zdeněk Fendrich, CSc Financial support:GAUK FRVŠ

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