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

Chen

2018

Pharmaceutical Biology

Context: Diclofenac and celastrol are always used together for the treatment of rheumatoid arthritis; the herb–drug interaction potential between diclofenac and celastrol is still unknown.Objective: This study investigates the effects of diclofenac on the pharmacokinetics of celastrol in rats.Materials and methods: Twelve male Sprague-Dawley rats were divided into two groups and received celastrol (1 mg/kg) or both celastrol (1 mg/kg) and diclofenac (10 mg/kg) by oral gavage, and blood samples were collected via the oculi chorioideae vein and determined using the LC-MS method developed in this study. Additionally, the effects of diclofenac on the transport of celastrol were investigated using a Caco-2 cell transwell model.Results: Diclofenac could significantly (p < 0.05) decrease the Cmax (from 66.93 ± 10.28 to 41.25 ± 8.06 ng/mL) and AUC0-t (from 765.84 ± 163.61 to 451.33 ± 110.88 μg × h/L) of celastrol in rats. The efflux ratio of celastrol increased significantly (p < 0.05) from 3.12 to 4.55 with the treatment of diclofenac.Discussion and conclusion: These results indicated that diclofenac could decrease the system exposure of celastrol in rats when they are co-administered, and these effects might be exerted via decreasing its absorption in intestine.

Section: Introductionsupporting

confidence: 68%

“…Celastrol is a substrate of P-gp (Li et al. 2016 ; Yan et al. 2017 ), and therefore, we infer that diclofenac might also decrease the system exposure of celastrol through inducing the activity of P-gp as P - gp could hinder its absorption in intestine.…”

Section: Resultsmentioning

confidence: 81%

Effects of diclofenac on the pharmacokinetics of celastrol in rats and its transport

Chen

2018

Pharmaceutical Biology

Evidence-Based Complementary and Alternative Medicine

“…P-glycoprotein (P-gp) has been confirmed as one of the main transporters that influencing drug transport in the intestine [36]. The P-gp inhibitor verapamil may significantly increase the transport of some compounds from the AP to BL side.…”

Section: Resultsmentioning

confidence: 99%

Elucidation of the Intestinal Absorption Mechanism of Loganin in the Human Intestinal Caco‐2 Cell Model

Yuan

Jia

et al. 2018

Loganin, iridoid glycosides, is the main bioactive ingredients in the plant Strychnos nux-vomica L. and demonstrates various pharmacological effects, though poor oral bioavailability in rats. In this study, the intestinal absorption mechanism of loganin was investigated using the human intestinal Caco-2 cell monolayer model in both the apical-to-basolateral (A-B) and the basolateral-to-apical (B-A) direction; additionally, transport characteristics were systematically investigated at different concentrations, pHs, temperatures, and potential transporters. The absorption permeability (PappAB) of loganin, which ranged from 12.17 to 14.78 × 10−6cm/s, was high at four tested concentrations (5, 20, 40, and 80μM), while the major permeation mechanism of loganin was found to be passive diffusion with active efflux mediated by multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP). In addition, it was found that loganin was not the substrate of efflux transporter P-glycoprotein (P-gp) since the selective inhibitor (verapamil) of the efflux transporter exhibited little effects on the transport of loganin in the human intestinal Caco-2 cells. Meanwhile, transport from the apical to the basolateral side increased 2.09-fold after addition of a MRP inhibitor and 2.32-fold after addition of a BCRP inhibitor. In summary, our results clearly demonstrate, for the first time, a good permeability of loganin in the human intestinal Caco-2 cell model and elucidate, in detail, the intestinal absorption mechanism and the effects of transporters on iridoid glycosides compounds.

“…The monolayer of Caco-2 cells formed on microporous filters is a widely used cell model in the study of drug transport and the interaction of P-gp and drugs [33-35]. However, Caco-2 cannot always correctly identify P-gp substrates due to the low expression of P-gp in Caco-2 cultures.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Benzaldehyde, Vanillin, Muscone and Borneol on P-Glycoprotein in Caco-2 Cells and Everted Gut Sac

Tan

et al. 2018

Pharmacology

Aims: In clinical practice, herbal medicines have played an important role in the modulation of drug transporters through the combination of conventional prescription drugs, which necessitates the elucidation of herb-drug interactions. The present study was designed to investigate the inhibitory effects and mechanisms of benzaldehyde, vanillin, muscone, and borneol on P-glycoprotein (P-gp). Methods: The effects of the 4 compounds on the intracellular accumulation of rhodamine-123 (Rho-123) in vinblastine-treated Caco-2 (VB-Caco-2) cells were studied by monitoring fluorescence intensity through a flow cytometry assay, and the effects of these compounds on Rho-123 transport through VB-Caco-2 monolayers and Rho-123 intestinal absorption in the rat everted gut sac were investigated by high-performance liquid chromatography. Moreover, P-gp expression in VB-Caco-2 cells was assessed using flow cytometry and Western blot analysis, and the relative ABCB1 mRNA level was determined by Real-time RT-PCR. Key Findings: The results showed that benzaldehyde, vanillin, muscone, and borneol significantly increased Rho-123 uptake in VB-Caco-2 cells, increased the absorption rate and apparent permeability coefficient of Rho-123 in rat jejunum and ileum, and decreased the efflux ratio of Rho-123 from 6.52 to less than 2 during transport across VB-Caco-2 cell monolayers. In addition, these compounds reduced the protein and ABCB1 mRNA levels of P-gp in VB-Caco-2 cells. Conclusions: These data indicate that benzaldehyde, vanillin, muscone and borneol could effectively reverse multidrug resistance via inhibiting the P-gp function and expression pathway. The data provide fodder for further investigation into the interaction between the 4 compounds and other drugs transported by P-gp.