Percorrer por autor "Domingues, Susana"
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- Enantiomeric biodistribution and toxicity of 3-chloromethcathinone (3-CMC) in Wistar rats after acute exposure – preliminary dataPublication . Langa, Ivan; Rocha-Pereira, Carolina; Milhazes, Nuno; Silva, Diana Dias da; Domingues, Susana; Silva, Paula; Barbosa, Joana; Faria, Juliana; Tiritan, Maria Elizabeth; Ribeiro, Cláudia; Dias da Silva, Diana CristinaThere has been a surge in global attention to New Psychoactive Substances (NPS) [1]. Synthetic cathinones stand out as a widely consumed NPS class. Notably, 3-chloromethcathinone (3-CMC) accounted for over 34% of NPS seizures in 2021 [2], which underscores concerns regarding its consumption and health effects. Of note, 3-CMC is chiral and mostly sold as a racemate. As human me-tabolism and pharmacological effects can be enantioselective [3], determination of the impact of enanti-oselectivity in toxicokinetics/toxicodynamics is essential for the assessment of 3-CMC effects. This work aimed to evaluate in vivothe enantioselective biodistribution and toxicity of racemic 3-CMC, after an acute exposure to 3-CMC. Ten-week-old male Wistar rats were administered intraperitoneally with saline or 3-CMC (10 or 20 mg/kg; n=6). Twenty-four hours after, animals were deeply anesthetized and nine organs (brain, liver, kidneys, lungs, heart, spleen, gut, muscle, adipose tis-sue), blood and urine were collected. For evaluation of the enantiomeric biodistribution, a previous in houseestablished indirect method by gas chromatography [3], was adapted and validated. Some biochem-ical analysis was performed using an analyser, whereas TBARS, ATP, glutathione and total protein were determined by spectrophotometry. Organs were also processed for histological analysis. After 24 h, 3-CMC was not found in most organs. Both enantiomers were detected in urine with one dominant enantiomer, suggesting enantioselectivity in metabolism. The histopathological results showed possible central chromatolysis in the brain (20 mg/kg), liver inflammation, renal lesions, lungs’ haemoptysis, and alveolar haemorrhage, in most 3-CMC-exposed animals. No differences were observed inthe heart. Our findings show rapid 3-CMC renal elimination, with enantio selectivity in metabolism. Alt-hough biochemical evaluations are ongoing, the results are expected to give further insights on the 3-CMC toxicity and histological abnormalities found in the brain, kidneys, liver and lungs.
- Enantiomeric biodistribution, metabolic profile, and toxicity of 3-chloromethcathinone in Wistar rats following acute exposurePublication . Langa, Ivan; Rocha-Pereira, Carolina; Silva, Paula; Milhazes, Nuno; Silva, Diana Dias da; Domingues, Susana; Resende, Albina Dolores; Barbosa, Joana; Faria, Juliana; Tiritan, Maria Elizabeth; Ribeiro, Cláudiaynthetic cathinones are a class of new psychoactive substances (NPS) with 3-chloromethcathinone (3-CMC) accounting for over 46% of NPS-related seizures in 2023. Sold as a racemate, 3-CMC exhibits enantioselective metabolism and pharmacological effects, making enantioselectivity a critical factor in evaluating its toxicokinetics and toxicodynamics. This study aimed to evaluate the enantiomeric biodistribution, metabolic profile, and toxicity of 3-CMC racemate in Wistar rats following acute exposure. For this purpose, a gas chromatography–mass spectrometry (GC–MS) method was validated for quantifying 3-CMC in biological matrices and for characterizing its biodistribution in vivo. Rats were intraperitoneally administered with saline (control) or 3-CMC (10 or 20 mg kg−1, b.w.). Animals were sacrificed 24 h after administration, and plasma, urine, and tissues were collected for biodistribution, biochemical, and histopathological analyses. 3-CMC was exclusively detected in the urine, along with three additional pairs of enantiomeric metabolites. Both 3-CMC and its metabolites exhibit enantiomeric fractions (EF) different from 0.5, indicating enantiomeric enrichment. Administration of 3-CMC significantly decreased plasma levels of creatine kinase-MB, alkaline phosphatase, and aspartate aminotransferase, along with increased levels of glucose and urea. In the urine, decreased levels of albumin were observed. Oxidative stress and energy biomarkers were altered in the brain, lungs, and kidneys. Histopathological analysis revealed morphological alterations in the brain, liver, and lungs at both doses, and in the kidneys at the highest dose. However, no significant alterations were observed in the other tissues. Taken together, our findings suggest enantioselective metabolism and indicate that, although rapidly eliminated by the kidneys, 3-CMC still causes significant toxicity in target organs, such as the brain, liver, lungs, and kidneys. This highlights the high toxicity of the drug or its metabolites, even over short-term exposure.