Inhibitory mechanisms of celastrol on human liver cytochrome P450 1A2, 2C19, 2D6, 2E1 and 3A4

Abstract

1. The present study was conducted to examine the possibility of herb-drug interaction by celastrol, which is a main compound isolated from Tripterygium wilfordii Hook F. using human liver microsomes with cocktail methods. Focused on its inhibitory manner on the metabolism of model probe substrates of five cytochrome P450 isoenzymes (CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in vitro which are important with the metabolism of different xenobiotics. 2. The results showed that celastrol inhibited the five types of human cytochrome P450 isoforms, with the IC50 values of 2.65 μM (CYP3A4), 5.99 μM (CYP2C19), 6.27 μM (CYP2D6), 7.66 μM (CYP1A2) and 9.38 μM (CYP2E1), respectively. The data indicated that celastrol acted in different manners as an inhibitor of human cytochrome P450 isoforms, which showed that celastrol not only un-competitively inhibited the CYP1A2 and 2E1 activities, but also competitively inhibited the CYP2C19 and 2D6 activities with Ki values of 1.41, 2.29, 5.27 and 4.21 μM, respectively. Celastrol was also a mixed-type inhibitor of CYP3A4, with Ki and Kis values of 2.02 and 5.49 μM, respectively. 3. Celastrol has the potential to inhibit cytochrome P450 activities and may cause the herb-drug interactions. Therefore, the use of celastrol and its preparations with conventional medicines should thus be taken in to account.

Evaluation of the Effects of Apatinib on the Pharmacokinetics of Venlafaxine and O‐desmethylvenlafaxine in SD Male Rats by UPLC–MS/MS

“…A single dose of Apa increased the AUC (0‐t) , AUC (0‐∞) and Cmax of Ven significantly, while Vz/F and CLz/F were decreased, indicating inhibition of Apa on Ven. The in vitro study also indicated that the inhibitory effect of Apa on Ven in RLM and HLM was both strong with IC 50 <10 μM , making a good accordance with the in vivo pharmacokinetics study. Interestingly, the influence of multiple dose of Apa on Ven was not that obvious, with only CLz/F decreased and Cmax increased.…”

Elucidation of the Intestinal Absorption Mechanism of Celastrol Using the Caco-2 Cell Transwell Model

“…Pharmacokinetic investigations indicated that celastrol is poorly absorbed and the bioavailability of celastrol is low [6][7][8]. The metabolic profile of celastrol has been investigated [9][10][11]. However, little information is available regarding the intestinal absorption mechanisms.…”

CYP450s-Activity Relations of Celastrol to Interact with Triptolide Reveal the Reasons of Hepatotoxicity of Tripterygium wilfordii

“…That is to say, the hepatotoxicity caused by celastrol is directly related to its accumulation in the liver cells. To be an inhibitor of CYP450s [35], celastrol could worsen hepatotoxicity caused by triptolide. As mentioned before, triptolide (not more than 10 μg) is used as the quality control and limited indicator for Tripterygium polycoride tablets, due to the presence of plentiful celastrol, it could lower the minimum concentration of triptolide that leads to decreased cell viability.…”