LC-MS/MS method for determination of cyclin-dependent kinase inhibitors, BP-14 and BP-20, and its application in pharmacokinetic study in rat

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F18%3A10383163" target="_blank" >RIV/00216208:11160/18:10383163 - isvavai.cz</a>

Alternative codes found

RIV/61389030:_____/18:00491930 RIV/61989592:15310/18:73592363

Result on the web

<a href="http://www.sciencedirect.com/science/article/pii/S1570023217320391" target="_blank" >http://www.sciencedirect.com/science/article/pii/S1570023217320391</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jchromb.2018.04.049" target="_blank" >10.1016/j.jchromb.2018.04.049</a>

Result language

angličtina

Original language name

LC-MS/MS method for determination of cyclin-dependent kinase inhibitors, BP-14 and BP-20, and its application in pharmacokinetic study in rat

Original language description

N-2-(4-Amino-cyclohexyl)-9-cyclopentyl-N-6-(6-furan-2-yl-pyridine-3-ylmethyl)-9H-purine-2,6-diamine (BP-14) and 2-(5-([2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purine-6-ylamino]-methyll-pyridine-2-y1)-phenol (BP-20) are novel cyclin-dependent kinase inhibitors, structurally related to roscovitine, with significant biological activity. A simple, selective and sensitive liquid chromatography - tandem mass spectrometry method for determining them in rat plasma, using roscovitine as an internal standard, was developed and validated. Chromatographic separation was performed in reversed phase mode on Acquity BEH C18 column (100 x 2.1 mm, 1.7 mu m) by gradient elution with mobile phases composed of 15 mM ammonium formate pH 4.0 and methanol at flow rate 0.25 mL/min at 40 degrees C. The analytes were detected based on their characteristic multiple reaction monitoring transitions in positive electrospray ionization mode m/z 473.07 &gt; 157.93 for BP-14, m/z 499.62 &gt; 184.2 for BP-20 and m/z 355.5 &gt; 90.86 for internal standard. In plasma the method provided good linearity within the entire concentration range: 1-10,000 nmol/L (r(2) = 0.9989) for BP-14 and 10-25,000 nmol/L (r(2) = 0.9994) for BP-20; the limit of detection was 0.6 nmol/L for BP-14 and 6.1 nmol/L for BP-20. Validation was also performed in bile and urine. The results of validation fit within the acceptance limits following European Medicines Agency guidelines. The method was applied in a pharmacokinetic study of BP-14 and BP-20 in vivo in rats following intravenous and intraduodenal administration including plasma pharmacokinetics, tissue distribution and excretion (renal and biliary). Both compounds showed low bioavailability after intraduodenal administration (0.630 and 1.58% for BP-14 and BP-20, respectively). Distribution into all the analyzed tissues (brain, lungs, liver, kidney, spleen, muscle, adipose tissue) was observed 3 h after single dose administration, the highest and lowest concentrations being reached in the adipose tissue and brain, respectively. The biliary excretion of the parent BP-14 and BP-20 compounds accounted for 4.81% and 10.6% of the doses, respectively, and renal excretion for &lt; 0.5% in both cases. The obtained results represent pilot knowledge for further development of a new generation of compounds with strong anticancer activities.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10406 - Analytical chemistry

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Chromatography B

ISSN

1570-0232

e-ISSN

—

Volume of the periodical

1089

Issue of the periodical within the volume

July

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

9

Pages from-to

24-32

UT code for WoS article

000435059300004

EID of the result in the Scopus database

2-s2.0-85046679927