Affiliations 

  • 1 Division of Applied Biomedical Sciences and Biotechnology, International Medical University, Kuala Lumpur, Malaysia
  • 2 Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Selangor, Malaysia
  • 3 Division of Biomedical Science, University of Nottingham Malaysia Campus, Semenyih, Selangor, Malaysia
  • 4 School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000Kuala Lumpur, Malaysia
Drug Metab Pers Ther, 2021 Apr 08.
PMID: 33831979 DOI: 10.1515/dmdi-2020-0182

Abstract

OBJECTIVES: Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug-natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6.

METHODS: CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6-antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking.

RESULTS: The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and K i values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 μM and K i =32.27 μM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro-in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition.

CONCLUSIONS: Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.