Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P‐glycoprotein

Ye, Ling; Wang, Tao; Tang, Lan; Liu, Wei; Yang, Zhen; Zhou, Juan; Zheng, Zhijie; Cai, Zheng; Hu, Ming; Liu, Zhongqiu

doi:10.1002/jps.22693

Cited by 116 publications

(93 citation statements)

References 25 publications

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“…Andrographolide and diverse other extractable secondary metabolites of A. paniculata possess bactericidal, fungicidal and antiviral activities (Sareer et al 2012), and oral bioavailability of andrographolide (as judged by its observed blood levels after oral intake) is low (Panossian et al 2000;Ye et al 2011). Andrographolide modulates physiological functions of diverse drug metabolising enzymes in liver and other peripheral organs as well (Pekthong et al 2008), and binds covalently with cellular metabolites and enzymes (Xia et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of anAndrographis paniculataextract and andrographolide on cognitive functions in streptozotocin-induced diabetic rats

Thakur

Rai

Chatterjee³

et al. 2016

Pharmaceutical Biology

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Context Andrographolide containing Andrographis paniculata (Burm. F.) Wall. Ex Nees (Acanthaceae) extracts is often used for treatments of diabetes and other inflammatory disorders commonly accompanying cognitive and other psychiatric disorders.Objective To compare the efficacies of a standardised A. paniculata extract (AP) and pure andrographolide on cognitive functions, oxidative stress and cholinergic function in diabetic rats. Materials and methods Streptozotocin-induced diabetic Charles Foster albino rats treated orally with a hydro-methanolic A. paniculata leaf extract (50, 100 and 200 mg/kg/day), or with pure andrographolide (15, 30 and 60 mg/kg/day) for 10 consecutive days, were subjected to Morris water maze test. After the test, acetylcholinesterase, superoxide dismutase (SOD), and catalase (CAT) activities and lipid peroxidation (LPO) in brain tissues were assessed. Results Acetylcholinesterase activity in pre-frontal cortex and hippocampus of diabetic rats was 2.1 and 2.6 times higher compared to nondiabetic rats. LPO was 1.6 times higher and decreased SOD (56.3%) and CAT (44.9%) activities in pre-frontal cortex of diabetic rats compared to nondiabetic rats. AP or andrographolide treatments dose dependently attenuated cognitive deficits, reduced acetylcholinesterase activity, oxidative stress, improved diabetic hyperglycemia and insulin deficiency. All observed effects of AP were quantitatively almost equal to those expected from its analytically quantified andrographolide content. Discussion and conclusion Reported observations are the very first ones suggesting beneficial effects of andrographolide against diabetes associated cognitive deficits, increased acetylcholinesterase activity and deteriorated antioxidative status. Efforts to exploit A. paniculata extracts enriched in andrographolide as preventive measures against such disorders can be warranted. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Beneficial effects of anAndrographis paniculataextract and andrographolide on cognitive functions in streptozotocin-induced diabetic rats

Thakur

Rai

Chatterjee³

et al. 2016

Pharmaceutical Biology

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“…17,18 However, the oral bioavailability of AG is low because of its low aqueous solubility (0.07 mg/mL in water) and low oral absorption due to rapid and extensive metabolism and efflux by P-glycoprotein (P-gp) in the intestine. 19,20 Thus, to overcome the problem of low oral bioavailability, improvements to the solubility of AG and prevention of its efflux by P-gp are urgently required.…”

Section: Introductionmentioning

confidence: 99%

Nanoemulsion as a strategy for improving the oral bioavailability and anti-inflammatory activity of andrographolide

Yen

Chen

et al. 2018

IJN

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Background Andrographolide (AG), a compound with low water solubility, possesses various pharmacological activities, particularly anti-inflammatory activity. However, its low oral bioavailability is a major obstacle to its potential use. This study developed and optimized an AG-loaded nanoemulsion (AG-NE) formulation to improve AG oral bioavailability and its protective effects against inflammatory bowel disease. Methods A high-pressure homogenization technique was used to prepare the AG-NE and solubility, viscosity, and droplet size tests were conducted to develop the optimized AG-NE composed of α-tocopherol, ethanol, Cremophor EL, and water. The permeability was assessed using everted rat gut sac method and in vivo absorption and anti-inflammatory effect in rats was also evaluated. The plasma concentration of AG was determined using our validated high performance liquid chromatography method, which was used to generate a linear calibration curve over the concentration range of 0.1–25 μg/mL in rat plasma ( R 2 >0.999). Results The optimized AG-NE had a droplet size of 122±11 nm confirmed using transmission electron microscopy and a viscosity of 28 centipoise (cps). It was stable at 4 and 25°C for 90 days. An ex vitro intestinal permeability study indicated that the jejunum was the optimal site for AG absorption from the optimized AG-NE, which was 8.21 and 1.40 times higher than that from an AG suspension and AG ethanol solution, respectively. The pharmacokinetic results indicate that the absorption of AG from AG-NE was significantly enhanced in comparison with that from the AG suspension, with a relative bioavailability of 594.3%. Moreover, the ulcer index and histological damage score of mice with indomethacin-induced intestinal lesions were significantly reduced by AG-NE pretreatment. Conclusion We conclude that the developed AG-NE not only enhanced the oral bioavailability of AG in this study but may also prove to be an effective formulation of AG for preventing gastrointestinal inflammatory disorders.

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“…5,6 The potential use of ADG has attracted wide attention in recent years. Unfortunately, the clinical use of ADG remains challenging due to its extremely poor solubility (1.32×10 -7 M in water at 25°C) and efflux by P-glycoprotein (P-gp), [7][8][9] which results in low bioavailability after oral administration.…”

Section: Introductionmentioning

confidence: 99%

Fabrication and in vitro/in vivo evaluation of amorphous andrographolide nanosuspensions stabilized by D-α-tocopheryl polyethylene glycol 1000 succinate/sodium lauryl sulfate

Qiao

Chen

Rui

et al. 2017

IJN

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Andrographolide (ADG) is a diterpenoid isolated from Andrographis paniculata with a wide spectrum of biological activities, including anti-inflammatory, anticancer and hepatoprotective effects. However, its poor water solubility and efflux by P-glycoprotein have resulted in lower bioavailability. In this study, ADG nanosuspensions (ADG-NS) were prepared using a wet media milling technique followed by freeze drying. d -α-Tocopheryl polyethylene glycol 1000 succinate (TPGS), a surfactant that inhibits P-glycoprotein function, and sodium lauryl sulfate were used as surface stabilizers. A Box–Behnken design was used to optimize the nanosuspension preparation. The products of these optimal preparation conditions were amorphous and possessed much faster dissolution in vitro than a coarse powder of ADG. The particle size and redispersibility index of the freeze-dried ADG-NS were 244.6±3.0 nm and 113%±1.14% (n=3), respectively. A short-term stability study indicated that the freeze-dried ADG-NS could remain highly stable as nanosuspensions during the testing period. A test of transport across a Caco-2 cell monolayer revealed that the membrane permeability ( P app ) of ADG-NS was significantly higher than the permeability of the ADG coarse powder or ADG-NS without TPGS ( P <0.01). Compared to the ADG coarse powder, a physical mixture, commercial dripping pills and ADG-NS without TPGS, ADG-NS exhibited significantly higher plasma exposure with significant enhancements in C max and area under the curve of plasma concentration versus time from zero to the last sampling time (AUC 0− t ) ( P <0.01). An evaluation of the anti-inflammatory effect on Carr-induced paw edema demonstrated that the ADG-NS were more effective in reducing the rate of paw swelling, producing a greater increase in the serum levels of nitric oxide (NO), Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) ( P <0.01) and an increase in superoxide dismutase activity ( P <0.05) compared to the ADG coarse powder. This study indicated that nanosuspensions could act as an effective delivery device for ADG to enhance its oral bioavailability and biological efficacy.

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Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P‐glycoprotein

Cited by 116 publications

References 25 publications

Beneficial effects of anAndrographis paniculataextract and andrographolide on cognitive functions in streptozotocin-induced diabetic rats

Beneficial effects of anAndrographis paniculataextract and andrographolide on cognitive functions in streptozotocin-induced diabetic rats

Nanoemulsion as a strategy for improving the oral bioavailability and anti-inflammatory activity of andrographolide

Fabrication and in vitro/in vivo evaluation of amorphous andrographolide nanosuspensions stabilized by D-α-tocopheryl polyethylene glycol 1000 succinate/sodium lauryl sulfate

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Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P‐glycoprotein

Cited by 116 publications

References 25 publications

Beneficial effects of anAndrographis paniculataextract and andrographolide on cognitive functions in streptozotocin-induced diabetic rats

Beneficial effects of anAndrographis paniculataextract and andrographolide on cognitive functions in streptozotocin-induced diabetic rats

Nanoemulsion as a strategy for improving the oral bioavailability and anti-inflammatory activity of andrographolide

Fabrication and in vitro/in vivo evaluation of amorphous andrographolide nanosuspensions stabilized by D-&alpha;-tocopheryl polyethylene glycol 1000 succinate/sodium lauryl sulfate

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Fabrication and in vitro/in vivo evaluation of amorphous andrographolide nanosuspensions stabilized by D-α-tocopheryl polyethylene glycol 1000 succinate/sodium lauryl sulfate