Influence of Verapamil on Pharmacokinetics of Triptolide in Rats

Zhang, Yichuan; Li, Jin; Lei, Xiaolin; Zhang, Tianying; Liu, Guangxian; Yang, Maolin; Liu, Min

doi:10.1007/s13318-015-0275-4

Cited by 22 publications

(11 citation statements)

References 29 publications

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“…Numerous natural compounds from medicinal herbs have been reported to be inhibitors of P-gp, and these compounds could enhance the oral bioavailability of P-gp substrates and also reverse multidrug resistance induced by chemotherapeutic agents [32,33]. There are several reports on the pharmacokinetic drug-drug interactions based on the inhibition or induction of transporters [34,35]; therefore, the effects of celastrol on the activity of P-gp should be elucidated. l " Fig.…”

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confidence: 99%

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

Liu

et al. 2016

Planta Med

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Celastrol, a triterpenoid isolated from stem (caulis) of Celastrus orbiculatus Thunb. (Celastraceae), has been known to have various pharmacological effects, including anti-inflammatory, anticancer, and antioxidant activities. However, the mechanism of the intestinal absorption of celastrol is unknown. The aim of this study was to investigate the intestinal absorption of celastrol using the Caco-2 cell transwell model. First, the bidirectional transport of celastrol in Caco-2 cell monolayers was observed. Then, the effects of time, concentration, temperature, paracellular pathway, and efflux transport inhibition on the transport of celastrol across the Caco-2 cell monolayers were investigated. The P-glycoprotein inhibitor verapamil and cyclosporin A, the multidrug resistance protein 2 inhibitor MK571, and the breast cancer resistance protein inhibitor reserpine were used. Additionally, the effects of celastrol on the activity of P-glycoprotein were evaluated using the rhodamine 123 uptake assay. In this study, we found that the intestinal transport of celastrol was a time- and concentration-dependent active transport. The paracellular pathway was not involved in the transport of celastrol, and the efflux of celastrol was energy dependent. The results indicated that celastrol is a substrate of P-glycoprotein but not multidrug resistance protein 2 or the breast cancer resistance protein. In addition, celastrol could not affect the uptake of rhodamine 123 in Caco-2 cells, which indicated that celastrol could not inhibit or induce the activity of P-glycoprotein.

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

Liu

et al. 2016

Planta Med

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“…Clinical trials using TPL for ADPKD indicated no noticeable changes in laboratory parameters indicative of possible toxicity and no sign of bone marrow suppression or liver toxicity (50). The toxicity and solubility of TPL could be improved using the nanoparticle coating method (51), pretreatment with verapamil (52) or CYP3A (53), or development of TPL analogues (54). Hence, we demonstrate that DKD patients with high serum/urine PTEN K27-polyUb could benefit from TPL-based treatment options to inhibit progression of renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease

et al. 2019

Journal of Clinical Investigation

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Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-β), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTEN K27-polyUb). Genetic inhibition of PTEN K27-polyUb alleviated Col4a3 knockout-, folic acid-, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTEN K27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTEN K27-polyUb facilitated dephosphorylation and protein stabilization of TWIST, SNAI1, and YAP in renal epithelial cells, leading to enhanced EMT. We identified that a small molecule, triptolide, inhibited MEX3C-catalyzed PTEN K27-polyUb and EMT of renal epithelial cells. Treatment with triptolide reduced TWIST, SNAI1, and YAP concurrently and improved kidney health in Col4a3 knockout-, folic acid-injured disease models and STZ-induced, BTBR ob/ob diabetic nephropathy models. Hence, we demonstrated the important role of PTEN K27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.

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“…Curculigoside (2 mg/mL) was dissolved in normal saline containing 0.5% methylcellulose and orally administered to rats at a dose of 20 mg/kg (Zhao et al 2014). The pretreated groups received oral verapamil (10 mg/kg) 30 min prior to curculigoside (Zhang et al 2015a(Zhang et al , 2015b. Verapamil was dissolved directly in normal saline at a concentration of 20 mg/mL.…”

Section: In Vivo Pharmacokinetic Studymentioning

confidence: 99%

“…There are several reasons for the poor bioavailability of a compound in the body, such as the low solubility and dissolution rate, poor permeability in intestine and fast elimination rate Shen et al 2015;Zhang et al 2015aZhang et al , 2015b. Several studies have been conducted to investigate the pharmacokinetic profiles of curculigoside in rats, and the results indicated that the oral bioavailability of curculigoside was poor (1-2%) (Zhao et al 2014;Yuan et al 2015).…”

Section: Introductionmentioning

confidence: 99%