School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Department of Chemistry, York College, City University of New York, New York, New York, USA.
Clin Transl Sci. 2024 Oct;17(10):e70043. doi: 10.1111/cts.70043.
Pedunculoside and rotundic acid, the most abundant components in plants of the genus Ilex L. (Aquifoliaceae), exhibit biological and pharmacological significance in the treatment of cardiovascular diseases. However, there have been few studies on their metabolism. This study performed a systematic metabolism study of pedunculoside and rotundic acid and evaluated their potential for herb-drug interaction. Pedunculoside or rotundic acid was incubated with human liver microsomes and recombinant human metabolic enzymes, and analyzed using LC-Q-TOF/MS and LC-MS/MS. Pedunculoside was found to be the most stable in human liver microsomes, whereas rotundic acid was easily metabolized. Eight pedunculoside metabolites and six rotundic acid metabolites were detected and tentatively identified through hydroxylation, glucuronidation, acetylation, and glucose conjugation. Hydroxylation of pedunculoside is mainly catalyzed by CYP3A4/5 and partly by CYP2C8. Hydroxylation of rotundic acid is almost exclusively catalyzed by CYP3A4/5, and its glucuronidation reaction is mediated by UGT1A4. Neither pedunculoside nor rotundic acid showed CYP inhibition (IC values > 50 μM) with the probe substrates of major CYP isoforms during incubation with human liver microsomes. This study is the first investigation into the in vitro metabolism of pedunculoside and rotundic acid using human liver microsomes. It also aims to assess their potential as perpetrators of drug-drug interactions involving CYP enzymes. The comprehensive metabolism and drug interaction studies of pedunculoside and rotundic acid enable us to evaluate and manage potential risks with their use in pharmacotherapy.
丁香苷和熊果酸是冬青属植物（冬青科）中最丰富的成分，在治疗心血管疾病方面具有重要的生物学和药理学意义。然而，关于它们的代谢研究较少。本研究对丁香苷和熊果酸进行了系统的代谢研究，并评估了它们作为药物相互作用的潜力。用人肝微粒体和重组人代谢酶孵育丁香苷或熊果酸，并用 LC-Q-TOF/MS 和 LC-MS/MS 进行分析。结果表明，丁香苷在人肝微粒体中最稳定，而熊果酸容易代谢。通过羟化、葡萄糖醛酸化、乙酰化和葡萄糖缀合等方式，检测并初步鉴定了 8 种丁香苷代谢物和 6 种熊果酸代谢物。丁香苷的羟化主要由 CYP3A4/5 催化，部分由 CYP2C8 催化。熊果酸的羟化几乎完全由 CYP3A4/5 催化，其葡萄糖醛酸化反应由 UGT1A4 介导。在用人肝微粒体孵育时，丁香苷和熊果酸均未显示对主要 CYP 同工酶探针底物的 CYP 抑制作用（IC 值>50 μM）。本研究首次用人肝微粒体研究了丁香苷和熊果酸的体外代谢，并评估了它们作为 CYP 酶介导的药物相互作用的潜在因素。丁香苷和熊果酸的全面代谢和药物相互作用研究使我们能够评估和管理其在药物治疗中的潜在风险。
