Introduction/Objectives: Procyanidins are abundant dietary flavonoids with diverse pharmacological activities; however, their Absorption, Distribution, Metabolism, and Excretion (ADME) remain incompletely characterized. MT-8, a procyanidin B3 derivative with an ethyl group at the C8 position of the A-ring, is a promising preclinical candidate for cerebral ischemia treatment and is currently in the Investigational New Drug (IND) application stage. This study aimed to systematically characterize the ADME profile of MT-8 in male Sprague-Dawley (SD) rats following intravenous administration to provide a reference for ADME studies of procyanidin-related compounds. Methods: A single intravenous dose of 24 mg/kg (100 μCi/kg) ¹⁴CMT-8 was administered to male SD rats. Given the observed instability of MT-8 in plasma due to catechol oxidation, 10 mM tris(2-carboxyethyl) phosphine hydrochloride (TCEP) was employed as a stabilizer in all sample preparations. Pharmacokinetics, tissue distribution, mass balance, metabolite profiling, and metabolic enzyme phenotyping were comprehensively evaluated. Results: Pharmacokinetic analysis revealed rapid elimination of ¹⁴CMT-8-related substances, with a terminal half-life of 1.77 hours. The blood-to-plasma radioactivity ratio (1.68) indicated preferential distribution into blood cells. Tissue distribution revealed the highest radioactivity concentrations in the small intestine, kidneys, and liver. Mass balance analysis showed total radioactive recovery of 95.49% within 168 hours, with clearance of >90% of drug-related substances within 24 hours, predominantly via feces (85.57%) and bile (62.78% in bile duct-cannulated rats), with only 9.91% in urine. Metabolite profiling identified 32 metabolites in plasma, urine, feces, and bile, with methylation and glucuronidation as the major metabolic pathways. In vitro phenotyping referred to catechol-O-methyltransferase (COMT) involvement in methylation and UDP-glucuronosyltransferase 1A1 (UGT1A1) and 1A9 (UGT1A9) in glucuronidation. Discussion: After verifying the mechanism of the instability of MT-8 in plasma, we tracked the in vivo disposition of MT-8 via radioisotope labeling technique and acquired credible pharmacokinetic, mass balance, tissue distribution, and metabolite identification results. Phenotypes of two enzymes were determined to further the investigation of the methylation and glucuronidation process of in vivo clearance of MT-8. Conclusion: Collectively, MT-8 undergoes rapid clearance, broad distribution, extensive metabolism, and predominant biliary/fecal excretion. These findings provide critical support for MT-8’s IND application and subsequent clinical development.
Xu et al. (Tue,) studied this question.
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