The anthraquinone drug rhein potently interferes with organic anion transporter-mediated renal elimination

Wang, Li; Pan, Xiaolei; Sweet, Douglas H.

doi:10.1016/j.bcp.2013.08.016

Cited by 31 publications

(18 citation statements)

References 27 publications

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“…The hepatobiliary excretory clearance (CL B ) or the renal excretory clearance (CL R ) was calculated by dividing the cumulative amount excreted into bile ( Cum.A e‐B,0–t ) or urine ( Cum.A e‐U,0–t ), respectively, by the plasma AUC 0–t . The drug–drug interaction index (DDI index) was calculated using the following equation (Giacomini et al ., ; Wang et al ., ):

DDI index = unbound C_{\max} \cdot R / {IC}_{50}

where unbound C max represents the maximal plasma unbound concentration after therapeutic dosing (μM), IC 50 represents the half maximal inhibitory concentration (μM) and R is the accumulative factor. R was calculated according to the following equation:

R = 1 / (1 - {normale}^{- k τ})

where k represents the elimination rate constant (0.693/ t 1/2 ) and τ is the dosing interval (h).…”

Section: Methodsmentioning

confidence: 99%

Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside‐perpetrated herb–drug interactions on OATP1B3

Jiang

Dong

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEGinsenosides are bioactive saponins derived from Panax notoginseng roots (Sanqi) and ginseng. Here, the molecular mechanisms governing differential pharmacokinetics of 20(S)-protopanaxatriol-type ginsenoside Rg1, ginsenoside Re and notoginsenoside R1 and 20(S)-protopanaxadiol-type ginsenosides Rb1, Rc and Rd were elucidated. EXPERIMENTAL APPROACHInteractions of ginsenosides with human and rat hepatobiliary transporters were characterized at the cellular and vesicular levels. A rifampin-based inhibition study in rats evaluated the in vivo role of organic anion-transporting polypeptide (Oatp)1b2. Plasma protein binding was assessed by equilibrium dialysis. Drug-drug interaction indices were calculated to estimate potential for clinically relevant ginsenoside-mediated interactions due to inhibition of human OATP1Bs. KEY RESULTSAll the ginsenosides were bound to human OATP1B3 and rat Oatp1b2 but only the 20(S)-protopanaxatriol-type ginsenosides were transported. Human multidrug resistance-associated protein (MRP)2/breast cancer resistance protein (BCRP)/bile salt export pump (BSEP)/multidrug resistance protein-1 and rat Mrp2/Bcrp/Bsep also mediated the transport of the 20(S)-protopanaxatriol-type ginsenosides. Glomerular-filtration-based renal excretion of the 20(S)-protopanaxatriol-type ginsenosides was greater than that of the 20(S)-protopanaxadiol-type counterparts due to differences in plasma protein binding. Rifampin-impaired hepatobiliary excretion of the 20(S)-protopanaxatriol-type ginsenosides was effectively compensated by the renal excretion in rats. The 20(S)-protopanaxadiol-type ginsenosides were potent inhibitors of OATP1B3. CONCLUSION AND IMPLICATIONSDifferences in hepatobiliary and in renal excretory clearances caused markedly different systemic exposure and different elimination kinetics between the two types of ginsenosides. Caution should be exercised with the long-circulating 20(S)-protopanaxadiol-type ginsenosides as they could induce hepatobiliary herb-drug interactions, particularly when patients receive long-term therapies with high-dose i.v. Sanqi or ginseng extracts.

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DDI index = unbound C_{\max} \cdot R / {IC}_{50}

R = 1 / (1 - {normale}^{- k τ})

where k represents the elimination rate constant (0.693/ t 1/2 ) and τ is the dosing interval (h).…”

Section: Methodsmentioning

confidence: 99%

Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside‐perpetrated herb–drug interactions on OATP1B3

Jiang

Dong

et al. 2015

British J Pharmacology

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“…In this case, a final precipitating factor leading to the onset of milk-alkali syndrome might have been the anthranoid laxatives. Chronic use of anthranoid laxatives can cause electrolyte imbalance and enhance the potassium depletion effect of diuretics [5,6] . Furthermore, some studies suggest that anthranoid laxatives can have nephrotoxic effects [7][8][9][10][11] , namely alteration of the calcium excretion mechanism.…”

Section: Discussionmentioning

confidence: 99%

Severe Milk-Alkali Syndrome in a Patient with Hypoparathyroidism Associated with 1,25(OH)2D, Hydrochlorothiazide and Anthranoid Laxative Consumption

Morini¹,

Donelli

Santi³

et al. 2017

European Journal of Case Reports in Internal Medicine

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Background Milk-alkali syndrome is a life-threatening condition defined by the triad of hypercalcaemia, metabolic alkalosis and acute renal failure, and is associated with consumption of calcium and absorbable alkali. Methods We report the case of a patient admitted to a step-down unit of a large hospital in Italy. Results The patient was a 59-year-old woman with hypoparathyroidism and mild chronic kidney insufficiency, treated for a preceding episode of hypocalcaemia with high doses of calcitriol and calcium carbonate, who was also taking hydrochlorothiazide and unreported herbal anthranoid laxatives. The patient was admitted to hospital with severe hypercalcaemia, severe metabolic alkalosis and acute renal insufficiency. The patient was successfully treated with urgent dialysis, loop diuretics and calcitonin administration. Conclusions This case underlines the need for caution when treating patients with impaired calcium metabolism regulation, and suggests that herbal anthranoid laxatives might act as triggers for milk-alkali syndrome. LEARNING POINTS Patients with hypoparathyroidism are more prone to develop milk-alkali syndrome. Patients need careful follow-up and review of their need for calcium supplements. Non-prescription and complementary medicines can aggravate hypercalcaemia.

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“…It is a monoterpenoid nucleus 1,8‐dihydroxyindole derivative containing two hydroxyl groups and one carboxyl group, which is highly polar and has electrochemical redox properties . These rhein‐containing herbs were widely used for the anti‐inflammatory, antifungal, antiallergic, antibacterial, antiviral, antidotal, antipyretic, and laxative properties in Asian countries including China, Korea, and Japan . This medicinal herb is also used to treat diabetic nephropathy .…”

Section: Introductionmentioning

confidence: 99%

“…10 These rhein-containing herbs were widely used for the anti-inflammatory, 11 antifungal, 12 antiallergic, 13 antibacterial, 14 antiviral, 15 antidotal, antipyretic, and laxative properties in Asian countries including China, Korea, and Japan. [16][17][18] This medicinal herb is also used to treat diabetic nephropathy. 19 However, in recent years, the reports of hepatotoxicity of P. multiflorum and its preparations containing rhein are common in the world.…”

Section: Introductionmentioning

confidence: 99%

Apoptotic effects of rhein through the mitochondrial pathways, two death receptor pathways, and reducing autophagy in human liver L02 cells

Shen

Bao

et al. 2019

Environmental Toxicology

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Rhein (4,5‐dihydroxyanthraquinone‐2‐carboxylic acid) is a major component of many medicinal herbs such as Rheum palmatum L. and Polygonum multiflorum. Despite being widely used, intoxication cases associated with rhein‐containing herbs are often reported. Currently, there are no available reports addressing the effects of rhein on apoptosis in human liver L02 cells. Thus, the aim of this study is to determine the cytotoxic effects and the underlying mechanism of rhein on human normal liver L02 cells. In the present study, the methyl thiazolyl tetrazolium assay demonstrated that rhein decreased the viability of L02 cells in dose‐dependent and time‐dependent ways. Rhein was found to trigger apoptosis in L02 cells as shown by Annexin V‐fluoresceine isothiocyanate (FITC) apoptosis detection kit and cell mitochondrial membrane potential (MMP) assay, with nuclear morphological changes demonstrated by Hoechst 33258 staining. Detection of intracellular superoxide dismutase activity, lipid oxidation (malondialdehyde) content, and reactive oxygen species (ROS) levels showed that apoptosis was associated with oxidative stress. Moreover, it was observed that the mechanism implicated in rhein‐induced apoptosis was presumably via the death receptor pathway and the mitochondrial pathway, as illustrated by upregulation of TNF‐α, TNFR1, TRADD, and cleaved caspase‐3, and downregulation of procaspase‐8, and it is suggested that rhein may increase hepatocyte apoptosis by activating the increase of TNF‐α level. Meanwhile, rhein upregulates the expression of Bax and downregulates the expression of procaspase‐9 and ‐3, and it is suggested that the mitochondrial pathway is activated and rhein‐induced apoptosis may be involved. In addition, we also want to explore whether rhein‐induced apoptosis is related to the autophagic changes induced by rhein. The results showed that rhein treatment increased P62 and decreased LC3‐II and beclin‐1, which means that autophagy was weakened. The results of our studies indicated that rhein induced caspase‐dependent apoptosis via both the Fas death pathway and the mitochondrial pathway by generating ROS, and meanwhile the autophagy tended to weaken.

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The anthraquinone drug rhein potently interferes with organic anion transporter-mediated renal elimination

Cited by 31 publications

References 27 publications

Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside‐perpetrated herb–drug interactions on OATP1B3

Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside‐perpetrated herb–drug interactions on OATP1B3

Severe Milk-Alkali Syndrome in a Patient with Hypoparathyroidism Associated with 1,25(OH)2D, Hydrochlorothiazide and Anthranoid Laxative Consumption

Apoptotic effects of rhein through the mitochondrial pathways, two death receptor pathways, and reducing autophagy in human liver L02 cells

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