Sodium tanshinone IIA sulfonate and its interactions with human CYP450s

Abstract

1.Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, a famous Chinese medicine used for many years to treat cardiovascular disorders. However, the role of cytochrome P450 (CYP) enzymes in the metabolism of STS was unclear. In this study, we screened the main CYPs for the metabolism of STS and studied their interactions in vitro.

2.Seven CYPs were screened for the metabolism of STS by human liver microsomes (HLMs) or recombinant CYP isoforms. To determine the potential of STS to affect CYP-mediated phase I metabolism in humans, phenacetin (CYP1A2), coumarin (CYP2A6), tolbutamide (CYP2C9), metoprolol (CYP2D6), chlorzoxazone (CYP2E1), S-Mephenytoin (CYP2C19), and midazolam (CYP3A4) were used as the respective probe substrates. Enzyme kinetic studies were performed to investigate the mode of inhibition of the enzyme–substrate interactions.

3.STS inhibited the activity of CYP3A4 in a dose-dependent manner in the HLMs and CYP3A4 isoform. Other CYP isoforms, including CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP2C19, showed minimal or no effect on the metabolism of STS.

4.The results suggested that STS primarily inhibits the activities of CYP3A4 in vitro, and STS has the potential to perpetrate drug–drug interactions with other CYP3A4 substrates.

Keywords:

• Chinese medicine
• CYP3A4
• drug–drug interaction
• sodium tanshinone IIA sulfonate

Declaration of interest

The authors have declared that no competing interests exist.

This work was supported by the National Scientific Foundation of China (Grants 81302850, 81300204, 31400306); the China Postdoctoral Science Foundation (Grants 2013M531817, 2014T70793); and the Science and Technology Plan Projects of Hunan Province (Grant 2014RS4011). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.