In vitro glycosidation potential towards olomoucine-type cyclin-dependent kinase inhibitors in rodent and primate microsomes

Červenková, Kateřina; Belejova, Marie; Chmela, Z; Rypka, M; Riegrová, D; Michnová, K; Michalíková, Klára; Súrová, I; Brejcha, A; Hanuš, Jan; Černý, Bohuslav; Fuksová, Květoslava; Havlı́cěk, Libor; Veselý, Jozef

doi:10.33549/physiolres.930268

Cited by 5 publications

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

LC–MS–MS identification of albendazole and flubendazole metabolites formed ex vivo by Haemonchus contortus

et al. 2008

View full text Add to dashboard Cite

Resistance of helminth parasites to common anthelminthics is a problem of increasing importance. The full mechanism of resistance development is still not thoroughly elucidated. There is also limited information about helminth enzymes involved in metabolism of anthelminthics. Identification of the metabolites formed by parasitic helminths can serve to specify which enzymes take part in biotransformation of anthelminthics and may participate in resistance development. The aim of our work was to identify the metabolic pathways of the anthelminthic drugs albendazole (ABZ) and flubendazole (FLU) in Haemonchus contortus, a world-wide distributed helminth parasite of ruminants. ABZ and FLU are benzimidazole anthelminthics commonly used in parasitoses treatment. In our ex vivo study one hundred living adults of H. contortus, obtained from the abomasum of an experimentally infected lamb, were incubated in 5 mL RPMI-1640 medium with 10 micromol L(-1) benzimidazole drug (10% CO(2), 38 degrees C) for 24 h. The parasite bodies were then removed from the medium. After homogenization of the parasites, both parasite homogenates and medium from the incubation were separately extracted using solid-phase extraction. The extracts were analyzed by liquid chromatography-mass spectrometry (LC-MS) with electrospray ionization (ESI) in positive-ion mode. The acquired data showed that H. contortus can metabolize ABZ via sulfoxidation and FLU via reduction of a carbonyl group. Albendazole sulfoxide (ABZSO) and reduced flubendazole (FLUR) were the only phase I metabolites detected. Concerning phase II of biotransformation, the formation of glucose conjugates of ABZ, FLU, and FLUR was observed. All metabolites mentioned were found in both parasite homogenates and medium from the incubation.

show abstract

LC–MS–MS identification of albendazole and flubendazole metabolites formed ex vivo by Haemonchus contortus

et al. 2008

View full text Add to dashboard Cite

show abstract

The natural cytokinin 2OH3MeOBAR induces cell death by a mechanism that is different from that of the “classical” cytokinin ribosides

Voller

Béres²,

Zatloukal³

et al. 2017

Phytochemistry

View full text Add to dashboard Cite

Metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitorR-roscovitine in the mouse

Nutley

Raynaud

Wilson

et al. 2005

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

R-roscovitine (seliciclib, CYC202) is a cyclin-dependent kinase inhibitor currently in phase II clinical trials in patients with cancer. Here, we describe its mouse metabolism and pharmacokinetics as well as the identification of the principal metabolites in hepatic microsomes, plasma, and urine. Following microsomal incubation of R-roscovitine at 10 μg/mL (28 μmol/L) for 60 minutes, 86.7% of the parent drug was metabolized and 60% of this loss was due to formation of one particular metabolite. This was identified as the carboxylic acid resulting from oxidation of the hydroxymethyl group of the amino alcohol substituent at C2 of the purine core present in R-roscovitine. Identification was confirmed by chemical synthesis and comparison of an authentic sample of the R-roscovitine-derived carboxylate metabolite (COOH-R-roscovitine). Other minor metabolites were identified as C8-oxo-R-roscovitine and N9-desisopropyl-R-roscovitine; these accounted for 4.9% and 2.6% of the parent, respectively. The same metabolic pattern was observed in vivo, with a 4.5-fold lower AUC∞ for R-roscovitine (38μmol/L/h) than for COOH-R-roscovitine (174 μmol/L/h). Excretion of R-roscovitine in the urine up to 24 hours post-dosing accounted for an average of only 0.02% of the administered dose of 50 mg/kg, whereas COOH-R-roscovitine represented 65% to 68% of the dose irrespective of the route of administration (i.v., i.p., or p.o.). A partially deuterated derivative (R-roscovitine-d9) was synthesized to investigate if formation of COOH-R-roscovitine could be inhibited by replacement of metabolically labile protons with deuterium. After 60 minutes of incubation of R-roscovitine-d9 or R-roscovitine with mouse liver microsomes, formation of COOH-R-roscovitine-d9 was decreased by ∼24% compared with the production of COOH-R-roscovitine. In addition, the levels of R-roscovitine-d9 remaining were 33% higher than those of R-roscovitine. However, formation of several minor R-roscovitine metabolites was enhanced with R-roscovitine-d9, suggesting that metabolic switching from the major carbinol oxidation pathway had occurred. Synthetic COOH-R-roscovitine and C8-oxo-R-roscovitine were tested in functional cyclin-dependent kinase assays and shown to be less active than R-roscovitine, confirming that these metabolic reactions are deactivation pathways.

show abstract

In vitro glycosidation potential towards olomoucine-type cyclin-dependent kinase inhibitors in rodent and primate microsomes

Cited by 5 publications

References 27 publications

LC–MS–MS identification of albendazole and flubendazole metabolites formed ex vivo by Haemonchus contortus

LC–MS–MS identification of albendazole and flubendazole metabolites formed ex vivo by Haemonchus contortus

The natural cytokinin 2OH3MeOBAR induces cell death by a mechanism that is different from that of the “classical” cytokinin ribosides

Metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitorR-roscovitine in the mouse

Contact Info

Product

Resources

About