Interaction between rhein acyl glucuronide and methotrexate based on human organic anion transporters.

Abstract

Rhein, a major bioactive compound of many medicinal herbs and the prodrug of diacerein, is often used with low dose of methotrexate as drug combination to treat rheumatoid arthritis. In this study, potential drug-drug interaction between methotrexate and rhein was investigated based on organic anion transporters (OAT). Our study demonstrated that rhein acyl glucuronide (RAG), the major metabolite of rhein in the human blood circulation, significantly inhibited the uptake of p-aminohippurate in hOAT1 transfected cells with IC50 value of 691 nM and estrone sulfate uptake in hOAT3 transfected cells with IC50 value of 78.5 nM. As the substrate of both hOAT1 and hOAT3, the methotrexate transport was significantly inhibited by RAG in hOAT1 transfected cells at 50 μM and hOAT3 transfected cells at 1 μM by 69% and 87%, respectively. Further in vivo study showed that after co-administrated with RAG in rats the AUC0-24 values of methotrexate increased from 3109 to 5370 ng/mL*hr and the t1/2 was prolonged by 40.5% (from 7.4 to 10.4 h), demonstrating the inhibitory effect of RAG on methotrexate excretion. In conclusion, rhein acyl glucuronide could significantly decrease the transport of methotrexate by both hOAT1 and hOAT3. The combination use of rhein, diacerein or other rhein-containing herbs with methotrexate may cause obvious drug-drug interaction and require close monitoring for potential drug interaction in clinical practice.

• Authors: Yuan Yuan, Hua Yang, Linghua Kong, Yuan Li, Ping Li, Hongjian Zhang, Jianqing Ruan
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 277 Pg. 79-84 (Nov 01 2017) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 28890383 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Anthraquinones
• Antirheumatic Agents
• Enzyme Inhibitors
• Glucuronides
• Organic Anion Transport Protein 1
• Organic Anion Transporters
• Organic Anion Transporters, Sodium-Independent
• SLC22A7 protein, human
• Methotrexate
• rhein

Topics

• Animals
• Anthraquinones (metabolism, pharmacology)
• Antirheumatic Agents (pharmacokinetics)
• Drug Interactions
• Enzyme Inhibitors (metabolism, pharmacology)
• Glucuronides (metabolism, pharmacology)
• HEK293 Cells
• Humans
• Male
• Methotrexate (pharmacokinetics)
• Organic Anion Transport Protein 1 (antagonists & inhibitors, metabolism)
• Organic Anion Transporters (antagonists & inhibitors, metabolism)
• Organic Anion Transporters, Sodium-Independent (antagonists & inhibitors, metabolism)
• Rats, Sprague-Dawley