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. Česko-Slovenské Farmakologické dny 30.8.-1.9.2005, Hradec Králové
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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. - PowerPoint PPT Presentation
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Evaluation of drug-drug interactions at the level of hepatic excretion
Stanislav Mičuda
Department of Pharmacology, Charles University in PragueFaculty of Medicine in Hradec Králové
55. Česko-Slovenské Farmakologické dny30.8.-1.9.2005, Hradec Králové
Clearance study left jugular v. (MTX 22 mol/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)
55. Farmakologické dny
MTX concentrations HPLC method with fluorescent detection *
Farmacokinetic analysis
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In vivo pharmacokinetics
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.
CLR/(fU x GFR) 2.2 0.3 1.6 0.2 + 0.7 0.7 0.2 B 0.4
Values are means SEM A P < 0.05; B P < 0.01; C P < 0.001
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Dexametazon 25 mg/kgOlive oilRat liver - mrp2 – Dex per os
Control Dexamethasone Parameter for image analysis
Centr Port Centr Port
Proportion of visual field area occupied by mrp2 staining
0.13 ± 0.05 2.11 ± 0.772 2.92 ± 0.88 C 3.91 ± 1.14 A
Integral optical densities of mrp2 in visual field
28 ± 11 467 ± 1742 664 ± 202 C 903 ± 266 A
Values are means ± SEM of 6 rats. Centr - pericentral areas; Port - periportal areas; 1P<0.05, 2P<0.001 periportal vs pericentral areas; AP<0.05, CP<0.001 comparison of data from respective locations between control and dexamethasone (25 mg/kg daily, p.o. for 4 days) pretreated animals.
BE 1.3-foldCLbile 1.1-foldHistol 3.1-foldWestern 2.4-fold
Pharmacokinetics of Rho-123
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Influence of DEXon P-gp activity
Control DEX 25 mg po
DIF (fold)
Urine flow rate (l/min) 26.0 4.0 96.0 12.0 C 3.6
UE rate (nmol/ml.kg-1) 0.10 0.04 0.28 0.06 B 2.7
Bile flow rate (l/min) 27.0 2.0 28.0 4.0 1.0
BE rate (nmol/ml.kg-1) 0.26 0.04 0.57 0.14 A 2.2
Plasma (M) 0.12 0.02 0.08 0.003 B 0.6
CLR (ml/min.kg-1) 0.71 0.24 3.70 0.68 B 5.2
CLBile (ml/min.kg-1) 2.22 0.34 7.88 2.29 A 3.5
CLTOT (ml/min.kg-1) 21.68 1.00 29.26 1.18 B 1.4
CLCR (ml/min.kg-1) 1.19 1.01 1.34 1.20 1.1
CLR/GFR 0.59 0.08 2.90 0.10 B 4.9
Values are means SEM A P < 0.05; B P < 0.01; C P < 0.001 Ctrl DEX
BE 2.2-foldCLbile 3.5-foldHistol 2.3-foldWestern 2.8-foldReal RT-PCR 3.1-fold
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