Title:

Determination of ADME processes of new H3 receptor antagonist from the group of piperidine derivatives

Author:

Szafarz, Małgorzata.

Subject:

DL76 ; histamine ; pharmacokinetics ; linearity ; P-glycoprotein

Abstract:

Pharmacokinetic studies are the integral part of preclinical evaluation of new compounds, potential drugs. The aim of this study was to determine pharmacokinetic properties of DL76 (nonimidazole H3 receptor antagonist) and to compare the values of bioavailability predicted in silico, based on the physicochemical characteristics of this compound, with the ones calculated from the in vivo experiment.At the beginning of this studies the analytical method (LC/MS/MS) enabling the quantification of DL76 in complex biological matrices was developed and validated. Then concentrations of the investigated compound were determined after intravenous (in the doses of 3, 6, 9 or 15 mg/kg) and intragastric (in the doses of 3, 6 or 9 mg/kg) administration of DL76 to rats. Based on the obtained data the pharmacokinetic parameters were calculated. The studies estimating the potential influence of P-glycoprotein on the disposition of DL76 were also conducted. The results of these studies show that the pharmacokinetics of DL76 in rats is non-linear in the range of administered doses. Distribution of DL76 in the investigated tissues was significant and uneven, with the highest values observed in lungs and the lowest in liver. Based on the performed studies it can be speculated that P-glycoprotein plays an important part in disposition of DL76 and that the CYP3A4 could be the main isoenzyme responsible for metabolism of this compound. DL 76 has very irregular bioavailability and predicted in silico values were in agreement with the ones calculated based on the in vivo experiment only for the lowest administered dose.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

farmakologia

Degree grantor:

Uniwersytet Jagielloński. Collegium Medicum. Wydział Farmaceutyczny. Zakład Farmakokinetyki i Farmacji Fizycznej.

Promoter:

Joanna Szymura-Oleksiak

Date:

2012

Date issued:

2012

Type:

Praca doktorska

Format:

application/pdf

Call number:

ZB-118166

ControlNumberVIRTUA:

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Language:

pol

Access rights:

nieograniczony

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

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