Neutrophil growth factors (NGFs) stimulate neutrophil growth and survival. The first synthetic cytokinin-derived NGF was recently discovered and is a prospective drug owing to its potential use in anti-inflammatory therapy. The metabolism of some cytokinin-derived drugs (e.g. R-roscovitine, olomoucine II) has already been studied and it has been shown that they may give rise to drug-drug interactions. In this in vitro study, the interactions of the novel neutrophil growth factor NGF1568 with two of the main classes of human drug-metabolizing enzymes, cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs), were tested. Of the CYPs evaluated, NGF1568 was found to inhibit only CYP2C9, by an uncompetitive mechanism and with a K(i) value of 349 μM. Formation of a glucuronide of NGF1568 was detected by LC/MS/MS analysis after it was incubated with human liver microsomes and UDP-glucuronic acid. The human recombinant UGT1A9 enzyme (major liver expression) and UGT1A7, UGT1A8, UGT1A10 enzymes (expressed in gastrointestinal tract instead of liver) were found to be responsible for NGF1568 glucuronidation. These results show that interaction of NGF1568 with CYPs is not as important as it is in the case of the cytokinin CDK inhibitors R-roscovitine and olomoucine II, but the conjugation enzymes (UGTs) play a major role in its metabolism. Thus, possible interference of NGF1568 with metabolism of other coadministered drugs at least on level of liver, kidney or intestinal UGTs should be thoroughly considered.

• MeSH
• adenosin analogy a deriváty   chemie   metabolismus   farmakologie   MeSH
• enzymatické testy MeSH
• glukuronidy chemie   metabolismus   farmakologie   MeSH
• glukuronosyltransferasa metabolismus   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• inhibitory cytochromu P450 MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• lidé MeSH
• puriny chemie   metabolismus   farmakologie   MeSH
• rekombinantní proteiny metabolismus   MeSH
• střeva enzymologie   MeSH
• subcelulární frakce účinky léků   enzymologie   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Imipenem je vysoce účinné širokospektré betalaktamové antibiotikum ze skupiny karbapenemů. Cílem naší práce bylo vyvinout v naší laboratoři spolehlivou a jednoduchou metodu ke stanovení plazmatických koncentrací imipenemu. Vzorky plazmy byly stabilizovány pomocí MOPS. Eluce probíhala v gradientovém módu, mobilní fáze byly tvořeny dihydrogenfosforečnanem draselným a metanolem. Detekce imipenemu probíhala při 313 nm bez interference cilastatinu nebo thienamycinu. Byly stanoveny základní charakteristiky týkající se validace metody.

Imipenem is a high-effective broad-spectrum carbapenem antibiotic. The aim of our study was to introduce a reliable and simple method for determination of imipenem plasma concentrations in our scientific laboratory. Plasma samples were stabilized by MOPS. Elution was performed in gradient mode, mobile phase composed of potassium dihydrogenphosphate and methanol. Imipenem was detected at 313 nm, no intereference of cilastatin or thienamycin was found. The basic validation parameters of method presented here have been also determined.

• Klíčová slova
• terapeutické monitorování,
• MeSH
• beta-laktamy aplikace a dávkování   farmakokinetika   krev   MeSH
• farmakokinetika MeSH
• imipenem aplikace a dávkování   farmakokinetika   krev   MeSH
• monitorování léčiv metody   normy   přístrojové vybavení   MeSH
• vysokoúčinná kapalinová chromatografie přístrojové vybavení   využití   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH

• Publikační typ
• abstrakty MeSH

Olomoucine II is a cyclin-dependent kinase inhibitor and a potential antineoplastic agent because it can arrest animal cell cycles. This study examines its interactions with human liver microsomal cytochrome P450 (P450) enzymes. Spectroscopic and high-performance liquid chromatography (HPLC) methods were used to estimate the degree of olomoucine II-mediated inhibition of enzymatic activities of eight drug-metabolizing P450s in vitro. In addition, mass spectrometry coupled with HPLC was used to identify an olomoucine II metabolite (2,5-dihydroxyroscovitine) formed in the reaction mixtures, and CYP3A4 was found to be responsible for the hydroxylation of the N(6)-benzyl ring at position 5, leading to this compound. Olomoucine II significantly inhibited the enzymatic activities of CYP1A2, CYP2C9, and (to a lesser degree) CYP3A4. The results indicate that use of olomoucine II as a drug could affect the activities of CYP3A4, CYP1A2, and CYP2C9 in vivo. Hence, the clinical relevance of these interactions should be carefully evaluated.

• MeSH
• antitumorózní látky farmakologie   MeSH
• aromatické hydroxylasy antagonisté a inhibitory   MeSH
• cytochrom P-450 CYP1A2 MeSH
• cytochrom P-450 CYP3A MeSH
• inhibiční proteiny cyklin-dependentních kinas farmakologie   MeSH
• inhibitory cytochromu P450 CYP1A2 MeSH
• inhibitory cytochromu P450 CYP3A MeSH
• inhibitory cytochromu P450 MeSH
• jaterní mikrozomy enzymologie   účinky léků   MeSH
• játra cytologie   enzymologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• N-demethylasy MeSH
• puriny farmakologie   MeSH
• substrátová specifita MeSH
• systém (enzymů) cytochromů P-450 MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH