The Phase I Biotransformation of the Potential Antileukotrienic Drug Quinlukast in Rat Microsomes and Hepatocytes

[img]PDF - Authorized users only
Language: English
128Kb
Title:The Phase I Biotransformation of the Potential Antileukotrienic Drug Quinlukast in Rat Microsomes and Hepatocytes
Creators:
Wsól, Vladimír
Szotáková, Barbora
Baliharová, Vendula
Šišpera, Luděk
Holčapek, Michal
Kolářová, Lenka
Suchanová, Bohumila
Kuchař, Miroslav
Skálová, Lenka
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 69, 3, pp. 689-702
Uncontrolled Keywords:Enzyme kinetics, Drug metabolism, Kinetic parameters, Microsomes, Metabolites, Antihistaminics, Biotransformations, Metabolic pathways, LC-MS, Antiasthmatics, Hepatocytes

Abstract

The phase I metabolism of quinlukast (VÚFB 19363, Q; 4-{[4-(2-quinolylmethoxy)phenyl]- sulfanyl}benzoic acid), a new antiasthmatic drug with significant antileukotriene effects, was&nbsp;investigated in rat microsomes and hepatocytes. Quinlukast, incubated with rat liver microsomal fraction under oxidative conditions, generated four metabolites, M2-M5. Based&nbsp;on comparison with synthetically prepared standards, metabolites M2 and M4 were identified as sulfoxide and sulfone of the parent compound, respectively. Metabolites M3&nbsp;and M5 were identified as quinlukast dihydrodiols. For all the metabolites the apparent kinetic parameters <i>K'</i><sub>m</sub>, <i>V'</i><sub>max</sub> and metabolic efficiency Cl<sub>int</sub> were calculated. No metabolite was found in rat liver cytosol. In vitro studies with primary cultures of isolated hepatocytes were designed to evaluate time dependent (2, 4, 8 and 24 h) and concentration dependent (0.005-0.1 mmol/l) formation of metabolites of quinlukast. Four metabolites were detected in culture medium. Three of them were identical to metabolites found in incubation of quinlukast with microsomes (M2, M3 and M5) and another, the most polar metabolite, M1, was detected. The basic metabolic pathways were proposed for quinlukast in rats. <p>

Title:The Phase I Biotransformation of the Potential Antileukotrienic Drug Quinlukast in Rat Microsomes and Hepatocytes
Creators:
Wsól, Vladimír
Szotáková, Barbora
Baliharová, Vendula
Šišpera, Luděk
Holčapek, Michal
Kolářová, Lenka
Suchanová, Bohumila
Kuchař, Miroslav
Skálová, Lenka
Uncontrolled Keywords:Enzyme kinetics, Drug metabolism, Kinetic parameters, Microsomes, Metabolites, Antihistaminics, Biotransformations, Metabolic pathways, LC-MS, Antiasthmatics, Hepatocytes
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:69
Number:3
Page Range:pp. 689-702
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc20040689UNSPECIFIED
ID Code:2237
Item Type:Article
Deposited On:06 Feb 2009 17:16
Last Modified:06 Feb 2009 16:16

Citation

Wsól, Vladimír; Szotáková, Barbora; Baliharová, Vendula; Šišpera, Luděk; Holčapek, Michal; Kolářová, Lenka; Suchanová, Bohumila; Kuchař, Miroslav; Skálová, Lenka (2004) The Phase I Biotransformation of the Potential Antileukotrienic Drug Quinlukast in Rat Microsomes and Hepatocytes. Collection of Czechoslovak Chemical Communications, 69 (3). pp. 689-702. ISSN 0010-0765

Repository Staff Only: item control page