Metabolomic Study of 7-Ethyl-9-(N-methyl)aminomethyl-10-hydroxycamptothecin Derivative (NMe)—The Chemotherapeutic Drug Candidate Versus Irinotecan (IR) on a Mouse Model
Piotr Surynt, Beata Naumczuk, Magdalena Popławska, Magdalena Urbanowicz, Katarzyna Unrug-Bielawska, Magdalena Cybulska-Lubak, Zuzanna Sadowska-Markiewicz, Jerzy Sitkowski, Elżbieta Bednarek, Natalia Zeber-Lubecka, Lech Kozerski, Michał Mikula, Jerzy Ostrowski
TL;DR
This study compares a new chemotherapy drug candidate, NMe, with irinotecan in mice, finding that NMe has a different and potentially safer metabolism profile.
Contribution
The study identifies novel NMe-specific metabolites and compares their pharmacokinetics with irinotecan, revealing potential therapeutic advantages.
Findings
NMe rapidly metabolizes and distributes more to the kidney and liver compared to irinotecan.
NMe produces higher levels of SN-38 glucuronides, which may reduce gastrointestinal toxicity.
Unique metabolites like 9-CH2-S-cysteine conjugate and NMe-formyl are specific to NMe.
Abstract
Background: In this study, we aimed to compare metabolomic profiles, biodistribution, and detoxification patterns of the novel SN-38 derivative NMe with irinotecan (IR), and to identify NMe-specific metabolites to evaluate its preclinical pharmacokinetic advantages. Methods: In vivo ADME studies were conducted for NMe, a 9-aminomethyl SN-38 derivative, and IR following a single intraperitoneal dose of 40 mg/kg in mice. Additionally, ADMET properties were predicted using ADMETlab and SwissADME tools for comparison. Levels of NMe and irinotecan absorbed into plasma, distributed to tissues, and metabolized were monitored in liver, lung, spleen, kidney, and stool samples at 15, 30, and 60 min post-administration. Tissue extracts were analysed using high-performance liquid chromatography (HPLC), liquid chromatography–electrospray ionization quadrupole time-of-flight-tandem mass spectrometry…
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Taxonomy
TopicsCancer therapeutics and mechanisms · Lung Cancer Research Studies · Synthesis and Biological Activity