Pharmacokinetics, Mass Balance, Tissue Distribution, and Metabolism of [3H]Catalpol in Rats: the Main Bioactive Component of Rehmannia glutinosa for the Treatment of Ischemic Stroke

Xinyu Ge; Yuandong Zheng; Yifei He; Chong Chen; Chen Yang; Saiwei Lu; Zhenyu Xuan; Dafang Zhong; Xingxing Diao

doi:10.2174/1389200224666230705142901

Pharmacokinetics, Mass Balance, Tissue Distribution, and Metabolism of [³H]Catalpol in Rats: the Main Bioactive Component of Rehmannia glutinosa for the Treatment of Ischemic Stroke

Curr Drug Metab. 2023;24(6):448-457. doi: 10.2174/1389200224666230705142901.

Authors

Xinyu Ge^{1

2}, Yuandong Zheng², Yifei He², Chong Chen^{1

2}, Chen Yang², Saiwei Lu³, Zhenyu Xuan^{4

5}, Dafang Zhong², Xingxing Diao^{1

2}

Affiliations

¹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
² Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
³ SuZhou Youseen New Drug R&D Co., Ltd., Suzhou 215123, China.
⁴ College of Pharmaceutical Sciences, Soochow University, Suzhou, 215127, China.
⁵ SuZhou Youseen New Drug R&D Co., Ltd., Suzhou, 215123, China.

PMID: 37409552
DOI: 10.2174/1389200224666230705142901

Abstract

Background: Catalpol, one of the main bioactive components isolated from Rehmannia glutinosa, was developed by Suzhou Youseen for the treatment of ischemic stroke; however, preclinical information about its absorption, distribution, metabolism, and excretion (ADME) in animals is inadequate.

Objective: This study aimed to illuminate the pharmacokinetics (PK), mass balance (MB), tissue distribution (TD), and metabolism of catalpol after a single intragastric administration of 30 mg/kg (300 μCi/kg) [³H]catalpol in rats.

Methods: Radioactivity in plasma, urine, feces, bile, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling was characterized by UHPLC-β-ram and UHPLC-Q-Exactive plus MS.

Results: The radio pharmacokinetic results showed that catalpol was rapidly absorbed by Sprague‒Dawley (SD) rats, with a median T_max of 0.75 h and an arithmetic mean half-life (_t1/2) of the total radioactivity of approximately 1.52 h in plasma. The mean recovery of the total radioactive dose was 94.82%±1.96% over 168 h postdose (57.52%±12.50% in the urine and 37.30%±12.88% in the feces). The parent drug catalpol was the predominant drugrelated substance in rat plasma and urine, while M1 and M2, two unidentified metabolites, were detected in feces. When [³H]catalpol was incubated with β-glucosidase and rat intestinal flora, we found that the same metabolites M1 and M2 were produced in both incubation systems.

Conclusions: Catalpol was excreted mainly through the urine. The drug-related substances were primarily concentrated in the stomach, large intestine, bladder, and kidney. Only the parent drug was detected in the plasma and urine, and M1 and M2 were detected in the feces. We speculate that the metabolism of catalpol in rats was mainly mediated by the intestinal flora, resulting in an aglycone-containing hemiacetal hydroxyl structure.

Keywords: rehmannia glutinosa; [³h]catalpol; intestinal flora; ischemic stroke.; mass balance; metabolism; tissue distribution.