Jouko Uusitalo

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The dramatically increased number of new chemical entities (NCE) used in drug discovery has raised a demand for efficient and rapid drug metabolism screening techniques. The aim of this study was to develop a global in vitro metabolic interaction screening test utilising the N-in-1 approach. A cocktail consisting of 10 CYP-selective probes with known(More)
HepaRG cells possess the unique property to differentiate in vitro and to express various functions of mature hepatocytes, including the major cytochromes P450 (P450s). In the present study, we carefully analyzed mRNA expression and activity of the major P450s and their responsiveness to three prototypical inducers, phenobarbital, rifampicin, and(More)
OBJECTIVE Our objective was to study the effect of the antiplatelet agents clopidogrel and ticlopidine on bupropion (INN, amfebutamone) hydroxylation, a probe reaction for cytochrome P450 (CYP) 2B6 activity. METHODS Twelve healthy male volunteers took a single 150-mg oral dose of bupropion either alone or after pretreatment with 75 mg clopidogrel once(More)
A sensitive and rugged LC/MSMS method was developed for a comprehensive in vitro metabolic interaction screening assay with N-in-1 approach reported earlier. A cocktail consisting of ten cytochrome P450 (CYP)-selective probe substrates with known kinetic, metabolic and interaction properties in vivo was incubated in a pool of human liver microsomes, and(More)
Drug metabolism profoundly affects drug action, because almost all drugs are metabolised in the body and thus their concentrations and elimination rates are dependent on metabolic activity. Drug metabolism contributes substantially to interindividual differences in drug response and is also often involved in drug interactions, resulting in either(More)
Practically all human hepatocyte cell lines are deficient in major cytochrome P450 (CYP)-related enzyme activities, making them unrepresentative of in vivo hepatocytes. We have used the recently developed HepaRG cell line to determine the spectrum of most important CYP enzyme activities involved in xenobiotic metabolism (CYP1A1/2, CYP2A6, CYP2B6, CYP2C8,(More)
A simple but efficient method for determination of labile protons in drug metabolites using post-column infusion of deuterium oxide (D2O) in liquid chromatography/mass spectrometry (LC/MS) experiments with electrospray ionization and time-of-flight mass spectrometry is described. The number of exchangeable protons in analytes, i.e. hydroxyl, amine, thiol(More)
Hypericum perforatum L. (St. John's Wort) has long been known as a medicinal plant, and has been used for the treatment of depression and neuralgic disorders. Its main active constituents are believed to be a naphthodianthrone, hypericin, and a phloroglucinol, hyperforin. A sensitive high performance liquid chromatography (HPLC)/electrospray tandem mass(More)
AIM Our objective was to study the effect of hormone replacement therapy and a combination oral contraceptive on the cytochrome P450 (CYP) 2B6 activity with bupropion (INN, amfebutamone) hydroxylation used as a probe reaction. METHODS This was a 3-way crossover study with 12 healthy female volunteers. The first phase was a control phase, in which all(More)
In vitro methods to produce metabolic information have increasingly been applied in toxicity risk assessment. In the current contract project of JRC/ECVAM In vitro-Toxicology Unit, 55 organic chemicals, mostly drugs and pesticides, most belonging to ECVAM/ICCVAM validation compounds, expected to be analyzable by LC-MS technique, were subjected to a(More)