Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The MOE Key Laboratory for Standardization of Chinese Medicines, 1200 Cailun Road, Shanghai 201203, China.
Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The MOE Key Laboratory for Standardization of Chinese Medicines, 1200 Cailun Road, Shanghai 201203, China; Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China.
J Pharm Biomed Anal. 2024 Dec 15;251:116447. doi: 10.1016/j.jpba.2024.116447. Epub 2024 Aug 22.
Cis-trans isomers of N-isobutyl-2E,4E,8Z,10E-dodecatetraenamide (DDA-E) and N-isobutyl-2E,4E,8Z,10Z-dodecatetraenamide (DDA-Z) are representative alkamides with numbness of tongue, anti-inflammatory and analgesic activities of Asari Radix et Rhizoma. However, their respective metabolic pathways and pharmacokinetic behaviors are still unknown. This study aim to investigate the metabolism of the two alkamides in vitro and in vivo using ultra-high-performance liquid chromatography-quadruple-time-of-flight mass spectrometry. Furthermore, a rapid, sensitive, and selective ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed to quantify DDA-E/Z in rat plasma. Results indicated that DDA-E and DDA-Z showed significant differences in metabolism and pharmacokinetics. Across all samples, 24 metabolites of DDA-E and 21 metabolites of DDA-Z were detected. A variety of pathways were involved in the production of these metabolites, mainly hydroxylation and oxidation. The linear range of DDA-E/Z was 1-2500 ng/mL (R = 0.9984), and the lowest quantification limit was 1 ng/mL. Precision, accuracy, extraction recovery, matrix effect, and stability of DDA-E/Z were within acceptable limits. Pharmacokinetic research was conducted using male Sprague-Dawley rats receiving intravenous (1 mg/kg) or intragastric (40 mg/kg) administration of DDA-E or DDA-Z solution. There was a calculated absolute bioavailability of 15.67 % for DDA-E and 4.83 % for DDA-Z when consumed orally. The apparent volume of distribution of intravenous and intragastric administrations were 4.44 ± 0.41 L/kg and 5.18 ± 0.67 L/kg for DDA-E, and 1.56 ± 1.66 L/kg and 2.35 ± 0.42 L/kg for DDA-Z. The maximal plasma concentrations of DDA-E and DDA-Z were 599.84 ± 149.92 nM and 422.09 ± 69.17 nM, and the time to maximum peak were 4.33 ± 3.51 h and 0.70 ± 1.12 h, respectively. In conclusion, in subsequent pharmacodynamics and safety evaluation studies, great attention should be paid to the metabolic characteristics and pharmacokinetic differences between DDA-E and DDA-Z.
顺反异构体 N-异丁基-2E,4E,8Z,10E-十二碳四烯酰胺（DDA-E）和 N-异丁基-2E,4E,8Z,10Z-十二碳四烯酰胺（DDA-Z）是细辛具有舌麻感、抗炎和镇痛活性的代表性酰胺类化合物。然而，它们各自的代谢途径和药代动力学行为仍不清楚。本研究旨在使用超高效液相色谱-四极杆飞行时间质谱法体外和体内研究这两种酰胺的代谢。此外，还建立了一种快速、灵敏、选择性的超高效液相色谱-串联质谱法来定量大鼠血浆中的 DDA-E/Z。结果表明，DDA-E 和 DDA-Z 在代谢和药代动力学方面存在显著差异。在所有样品中，检测到 DDA-E 的 24 种代谢物和 DDA-Z 的 21 种代谢物。这些代谢物的产生涉及多种途径，主要是羟化和氧化。DDA-E/Z 的线性范围为 1-2500ng/mL（R=0.9984），定量下限为 1ng/mL。DDA-E/Z 的精密度、准确度、提取回收率、基质效应和稳定性均在可接受范围内。使用静脉（1mg/kg）或口服（40mg/kg）给予 DDA-E 或 DDA-Z 溶液的雄性 Sprague-Dawley 大鼠进行药代动力学研究。口服时，DDA-E 的绝对生物利用度为 15.67%，DDA-Z 的绝对生物利用度为 4.83%。静脉和口服给药的表观分布容积分别为 DDA-E 的 4.44±0.41L/kg 和 5.18±0.67L/kg，以及 DDA-Z 的 1.56±1.66L/kg 和 2.35±0.42L/kg。DDA-E 和 DDA-Z 的最大血浆浓度分别为 599.84±149.92nM 和 422.09±69.17nM，达峰时间分别为 4.33±3.51h 和 0.70±1.12h。总之，在随后的药效学和安全性评价研究中，应高度关注 DDA-E 和 DDA-Z 之间的代谢特征和药代动力学差异。
