Piperine enhances the bioavailability of silybin via inhibition of efflux transporters BCRP and MRP2

Bi, Xiaoli; Yuan, Zhongwen; Qu, Biao; Zhou, Hua; Liu, Zhongqiu; Xie, Yu

doi:10.1016/j.phymed.2018.09.217

Cited by 50 publications

(32 citation statements)

References 37 publications

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“…The advancement of CCl 4 ‐actuated hepatotoxicity appears to depend mostly on the presence of free radicals and oxidative processes. Therefore, it is speculated that extracts/compounds having free radical scavenging and additionally antioxidant activities could likewise exhibit hepatoprotective effects against the CCl 4 poisonous impact . This is supported by the claim that the combination of hepatoprotective impact and antioxidant activity synergistically inhibits the process of commencement and advancement of hepatocellular damage.…”

Section: Discussionmentioning

confidence: 98%

Combination of metformin and luteolin synergistically protects carbon tetrachloride‐induced hepatotoxicity: Mechanism involves antioxidant, anti‐inflammatory, antiapoptotic, and Nrf2/HO‐1 signaling pathway

Yang¹,

Yang²,

Jiangmei³

2019

BioFactors

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Liver diseases are one of the fatal disorders due to the vital role of the liver. Carbon tetrachloride (CCl4) is the most perceived chemical substance utilized in developing models of hepatic damage. Metformin (Met) is a potent antidiabetic and redox modulatory agent that has shown anticancer and protective effects on various organs. Therefore, addition of therapy with natural antioxidative agents or herbal extracts shows defensive impacts against different injuries inside the body. Luteolin (Lut) can be found in several customary Chinese remedies. It has been reported for various pharmacological actions such as antitumor, antioxidative, and anti‐inflammatory impacts. Here, the liver injury rat model was established using CCl4 (1.00 mL/kg body weight) in vivo. The protective roles of Met and Lut separately or in combination were observed in hepatotoxicity induced by CCl4. The result was shown that both Met and Lut, while individually used, were normally active in diminishing CCl4‐caused hepatotoxicity. The combination of two drugs performed synergistically to improve liver damage caused by CCl4, as shown by the considerably improved liver dysfunction. Met and Lut showed highly antioxidative effects on CCl4‐treated rats moderately by increasing the activities and expression of the antioxidant enzymes. Along with this, a combination of Met and Lut significantly suppressed inflammatory responses, which is evidenced by the reduced level of inflammatory cytokines together with interleukin 1 beta (IL‐1β), tumor necrosis factor alpha (TNF‐α), and interleukin 6 (IL‐6). Additionally, CCl4‐agitated apoptosis was intensely reduced by Met and Lut through reducing cleaved caspase‐3 and Bax (pro‐apoptotic factor) while increasing Bcl‐2 (antiapoptotic factor) signaling pathways. Cotreatments of Met and Lut upregulated nuclear factor erythroid 2‐related factor 2 (NRF2) and heme oxygenase‐1 (HO‐1) expression in the CCl4‐intoxicated rat's liver. The above result recommended that combination of Met and Lut may have a substantial potential and synergizing impact against CCl4‐induced hepatotoxicity.

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Section: Discussionmentioning

confidence: 98%

Combination of metformin and luteolin synergistically protects carbon tetrachloride‐induced hepatotoxicity: Mechanism involves antioxidant, anti‐inflammatory, antiapoptotic, and Nrf2/HO‐1 signaling pathway

Yang¹,

Yang²,

Jiangmei³

2019

BioFactors

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“…Studies have shown that drugs inhibiting BCRP and MRP2, such as piperine or tangeretin [23,34], may lead to increased bioavailability of silybin. Similarly, enhanced-exposure of silybin occurred in patients with hepatic cirrhosis where transporter expression is also known to decrease [74].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies focus extensively on silybin interfering with the metabolism and disposition of other drugs. However, some studies in recent years revealed the likelihood that silybin may be influenced by certain compounds such as tangeretin [23], piperine [34], and baicalein [19]. New formulations of silybin containing these bio-enhancers [35] provide new therapeutic strategy.…”

Section: Silybin As a Beneficiary Of Ddimentioning

confidence: 99%

“…Piperine is the main component of black and long pepper that has attracted much attention in recent years for its inhibiting activities on efflux transporters and metabolic enzymes [37]. Bi and colleagues proved that piperine is not only an inhibitor of P-gp, but also an inhibitor of MRP2 and BCRP in Caco-2 model and MDCKII cell lines [34]. When silybin and piperine were co-administered, the maximum plasma drug concentration (C max ) and the area under the drug concentration–time curve up to time ‘t’( AUC 0-t ) of both silybin A and silybin B in rats were higher than that of silybin used alone [34].…”

Section: Silybin As a Beneficiary Of Ddimentioning

confidence: 99%

“…Bi and colleagues proved that piperine is not only an inhibitor of P-gp, but also an inhibitor of MRP2 and BCRP in Caco-2 model and MDCKII cell lines [34]. When silybin and piperine were co-administered, the maximum plasma drug concentration (C max ) and the area under the drug concentration–time curve up to time ‘t’( AUC 0-t ) of both silybin A and silybin B in rats were higher than that of silybin used alone [34]. A 76% increase in C max and a 37% increase in AUC 0-t of silybin A were observed, while C max and AUC 0-t of total silybin B were increased by 60% and 26%, respectively.…”

Section: Silybin As a Beneficiary Of Ddimentioning

confidence: 99%

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Metabolism, Transport and Drug–Drug Interactions of Silymarin

Xie

Zhang

et al. 2019

Molecules

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Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR−) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.

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Intestinal absorption pathways of lisinopril: Mechanistic investigations

Elewa

Osman

Essa

et al. 2022

Biopharm & Drug Disp

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Lisinopril is an antihypertensive drug with poor intestinal permeability. Enhancement of intestinal absorption depends on a clear understanding of the permeation pathways and absorption mechanisms. Unfortunately, these are not fully elucidated for lisinopril. Accordingly, the aim was to determine lisinopril permeation pathways and obstacles limiting membrane transport with subsequent nomination of appropriate permeation enhancers. This employed an in situ rabbit intestinal perfusion technique, which revealed site-dependent absorptive clearance (PeA/L) from a lisinopril simple solution (5 μg/ml), with paracellular absorption playing a role.Regional drug permeability ranked as colon> duodenum> jejunum> ileum opposing intestinal expression rank of P-glycoprotein (P-gp) efflux transporters. Duodenal and jejunal perfusion of a higher lisinopril concentration (50 μg/ml) reflected saturable absorption, suggesting carrier-mediated transport. The effect of piperine and verapamil as P-gp inhibitors on intestinal absorption of lisinopril was investigated. Coperfusion with either piperine or verapamil significantly enhanced lisinopril absorption, with enhancement being dominant in the ileum segment. This supported the contribution of P-gp transporters to poor lisinopril permeability. On the other hand, coperfusion of lisinopril with zinc acetate dihydrate significantly multiplied lisinopril PeA/L by 2.3-and 6.6-fold in duodenum and ileum segments, respectively, through magnifying intestinal water flux. The study explored the barriers limiting lisinopril intestinal absorption. Moreover, the study exposed clinically relevant lisinopril interactions with common coadministered cargos that should be considered for an appropriate lisinopril regimen. However, this requires further in vivo verification.

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Piperine enhances the bioavailability of silybin via inhibition of efflux transporters BCRP and MRP2

Cited by 50 publications

References 37 publications

Combination of metformin and luteolin synergistically protects carbon tetrachloride‐induced hepatotoxicity: Mechanism involves antioxidant, anti‐inflammatory, antiapoptotic, and Nrf2/HO‐1 signaling pathway

Combination of metformin and luteolin synergistically protects carbon tetrachloride‐induced hepatotoxicity: Mechanism involves antioxidant, anti‐inflammatory, antiapoptotic, and Nrf2/HO‐1 signaling pathway

Metabolism, Transport and Drug–Drug Interactions of Silymarin

Intestinal absorption pathways of lisinopril: Mechanistic investigations

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