2. Academic Validation
  3. 7-Hydroxycoumarin and its conjugated metabolites interact with organic anion transporters 1 and 3 in vitro and in vivo

7-Hydroxycoumarin and its conjugated metabolites interact with organic anion transporters 1 and 3 in vitro and in vivo

  • Chem Biol Interact. 2025 Jan 5:405:111293. doi: 10.1016/j.cbi.2024.111293.
Lijun Luo 1,  Yongchun Chang 2,  Weilin Zhang 3,  Xiao Liu 4,  Junpu Ge 5,  Jieyi Chen 6,  Yan Li 7,  Dan Zhang 8,  Li Sheng 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: luolijun@imm.ac.cn.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: cyongchun@imm.ac.cn.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: zhangweilin@imm.ac.cn.
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: liuxiao_tr@163.com.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: gjpbbml@163.com.
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: chenjieyi@imm.ac.cn.
  • 7 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: yanli@imm.ac.cn.
  • 8 Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: danzhang@imm.ac.cn.
  • 9 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: shengli@imm.ac.cn.
PMID: 39481674 DOI: 10.1016/j.cbi.2024.111293
Abstract

7-Hydroxycoumarin (7-HC) is a natural coumarin compound rich in Chinese herbal medicines and has various pharmacological activities. After oral administration of 7-HC in rodents, its conjugated metabolites 7-hydroxycoumarin-β-D-glucuronide (7-HCG) and 7-hydroxycoumarin sulfate (7-HCS), exhibit high systemic exposure and urinary excretion. Organic anion transporters 1 and 3 (OAT1 and OAT3), mainly expressed in the proximal renal tubules, play an important role in drug-drug interactions and drug-induced kidney injury. We aimed to explore the mechanisms of OAT-mediated drug interactions and renal protective mechanisms of 7-HC and its conjugates. OAT-overexpressing cell models revealed that 7-HC was not a substrate for OAT1 and OAT3, while 7-HCG was specifically transported by OAT3. In contrast, 7-HCS can be transported by both OATs. Besides, 7-HC significantly inhibited the activity of OAT1 and OAT3, while 7-HCS had a strong inhibitory effect on OAT1 (IC50 < 10 μM). After co-administration of 100 mg/kg of 7-HC to mice, systemic exposure and clearance of furosemide (a clinical substrate of OATs) were significantly increased and decreased, respectively. In addition, 7-HC decreased OAT-mediated cytotoxicity and reduced the renal distribution of adefovir in mice. Together, these findings will provide support for OAT-mediated drug interactions and the renal protection of 7-HC.

Keywords

Adefovir; Conjugates; Drug interactions; Nephrotoxicity; Organic anion transporter; Pharmacokinetics.

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