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Evaluation of drug-drug interactions at the level of hepatic excretion

55. Česko-Slovenské Farmakologické dny 30.8.-1.9.2005, Hradec Králové. Evaluation of drug-drug interactions at the level of hepatic excretion. Stanislav Mičuda. Department of Pharmacology, Charles University in Prague Faculty of Medicine in Hradec Králové. 55. Farmakologické dny.

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Evaluation of drug-drug interactions at the level of hepatic excretion

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  1. 55. Česko-Slovenské Farmakologické dny 30.8.-1.9.2005, Hradec Králové Evaluation of drug-drug interactions at the level of hepatic excretion Stanislav Mičuda Department of Pharmacology, Charles University in Prague Faculty of Medicine in Hradec Králové

  2. 55. Farmakologické dny Hepatic drug processing

  3. Inhibition – MDR1 Itraconazole Digoxin 0.125 mg + valspodar 400 mg  7-11 day Shon JH; Clin Pharmacol Ther 2005;78(2):191-201 Kovarik JM; Clin Pharmacol Ther 1999;66(4):391-400

  4. Induction – MDR1 Greiner B; J Clin Invest 1999;104(2):147-53.

  5. In vivo Preclinical - Clinical Studies • Single and Repeat Dose Pharmacokinetics • Drug Interaction Studies • Mass Balance Excretion Studies • Imaging Studies • In Situ Tissue Perfusions Mai I; Clin Pharmacol Ther 2004;76(4):330-40. Sasongko L; Clin Pharmacol Ther 2005;77(6):503-14. 99mTc-Sestamibi Scan following XR-9576

  6. 55. Farmakologické dny The aim of study influence of dexamethasone on expression and activity of mrp2 Dexamethasone – a synthetic corticosteroid, (t1/2 = 36-54 h), eliminated mainly in the unchanged form in urine – induction of mrp2 protein expression? Methotrexate (MTX) as a selective substrate for mrp2 Probenecid as an inhibitor of mrp2 SPC: 86698 DEXAMETHAZON LÉČIVA TBL 20X0.5MG-BLISTR LEX CZ

  7. 55. Farmakologické dny In vivo pharmacokinetics Wistar male rats (Konárovice) - 3 groups (N = 6)  Dex (25 mg/kg daily 4 days, p.o.), Control (Oliv. oil 4 days, p.o.), Probenecid  70 mmol/kg  3.33 mmol/min.kg-1 simultaneously with MTX Clearance study  left jugular v. (MTX 22 mmol/kg 164 nmol/kg.h-1 4 ml/min)  right a. carotis (blood sampling - since 55‘ - 10 min)  bladder (urine  0-90 min  10 min)  bile duct (bile  0-90 min  10 min)

  8. 55. Farmakologické dny In vivo pharmacokinetics MTX concentrations HPLC method with fluorescent detection * Farmacokinetic analysis CLtotal = Rinf / Css CLbil = Cbil . Vbil / Css CLren = CU.VU / Css BE = Cbil . Vbil UE = CU.VU CLRratio = CLren / GFR CLRratioU = CLren / (fU .GFR) CLRS = (CLren / fU) - GFR * Chladek J; J Chromatogr B Biomed Sci Appl 2000;744(2):307-13.

  9. 55. Farmakologické dny Probenecid 40 Control Dexamethasone 30 20 Methotrexate (uM) 10 0 60 70 80 90 100 Time (min) Pharmacokinetics of MTX in steady-state

  10. 55. Farmakologické dny Pharmacokinetics of MTX in steady-state

  11. 55. Farmakologické dny Rat liver - mrp2 – Dex per os Olive oil Dexametazon 25 mg/kg BE  1.3-fold CLbile 1.1-fold Histol  3.1-fold Western  2.4-fold

  12. 55. Farmakologické dny Influence of DEX on P-gp activity Pharmacokinetics of Rho-123 BE  2.2-fold CLbile  3.5-fold Histol  2.3-fold Western  2.8-foldReal RT-PCR  3.1-fold Ctrl DEX

  13. 55. Farmakologické dny Conclusion • Drug-drug interactions may be of great clinical importance • - A significant number is transport protein-mediated • in vivo studies – a complex view of pharmacokinetics • and mechanisms using model substrates • in vivo studies – verification of outcome from in vitro models • allowing predictions • - interspecies extrapolation • Glucocorticoids and MRP2 vs. MTX • induction of proteins without changes in pharmacokinetics of MTX

  14. 55. Farmakologické dny ACKNOWLEDGEMENTS Co-workers Leoš Fuksa Jolana Cermanová Eva Brčáková Jitka Hájková František Štaud Petr Pávek Lucie Mundlová Jan Osterreicher Jaroslav Mokrý Jaroslav Chládek Jiřina Martínková ...enjoy adventure of every experiment... Grants GAUK 89/2002/C MŠMT EC-B25.001

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