Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects.

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.

Flavonoid-statin interactions causing myopathy and the possible significance of OATP transport, CYP450 metabolism and mevalonate synthesis.

3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are a primary treatment for hyperlipidemic cardiovascular diseases which are a leading global cause of death. Statin therapy is life saving and discontinuation due to adverse events such as myotoxicity may lead to unfavourable outcomes. There is no known mechanism for statin-induced myotoxicity although it is theorized that it is due to inhibition of downstream products of the HMG-CoA pathway. It is known that drug-drug interactions with conventional medicines exacerbate the risk of statin-induced myotoxicity, though little attention has been paid to herb-drug interactions with complementary medicines. Flavonoids are a class of phytochemicals which can be purchased as high dose supplements. There is evidence that flavonoids can raise statin plasma levels, increasing the risk of statin-induced myopathy. This could be due to pharmacokinetic interactions involving hepatic cytochrome 450 (CYP450) metabolism and organic anion transporter (OATP) absorption. There is also the potential for flavonoids to directly and indirectly inhibit HMG-CoA reductase which could contraindicate statin-therapy. This review aims to discuss what is currently known about the potential for high dose flavonoids to interact with the hepatic CYP450 metabolism, OATP uptake of statins or their ability to interact with HMG-CoA reductase. Flavonoids of particular interest will be covered and the difficulties of examining herbal products will be discussed throughout.

Xanthine oxidase inhibitory activity and antihyperuricemic effect of Moringa oleifera Lam. leaf hydrolysate rich in phenolics and peptides.

ETHNOPHARMACOLOGICAL RELEVANCE: Moringa oleifera Lam. leaf (MOL), a rich source of protein and phenolics, was traditionally used to treat various diseases including headaches, fevers, sore throat and dyslipidemia. Recently, MOL was reported to possess antioxidant, anti-dyslipidemia and hepato-renal protective activities, indicating that MOL could become a potential agent to improve metabolic disorders associated with hyperuricemia. The antihyperuricemic effect of MOL hydrolysate (MOLH) with high contents of phenolics and peptides remains unknown. AIM OF THE STUDY: The aim of this study is to investigate xanthine oxidase (XO) inhibitory activity of MOLH, to clarify phenolic and peptide profiles of MOLH, and to evaluate possible mechanism underlying the antihyperuricemic effect of MOLH. MATERIALS AND METHODS: MOLH was prepared by enzymatic hydrolysis using commercial trypsin. XO inhibitory activity was determined by XO reaction-UPLC-MS coupling method. The chemical profiles of the phenolic and peptide fractions of MOLH were determined by UPLC-QTOF-MS/MS. The antihyperuricemic effect of MOLH was evaluated in a potassium oxonate-induced hyperuricemic rat model at doses of 200 and 500 mg/kg. Serum uric acid (UA), urea nitrogen, creatinine (CRE), triglyceride (TG), total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels, serum XO activity, liver malondialdehyde (MDA) equivalent level, renal tumor necrosis factor-α and interleukin-1ß levels, and protein expression of renal urate-anion transporter 1, glucose transporter 9 and ATP-binding cassette transporter G2 were determined. RESULTS: The phenolic and peptide fractions played key roles in inhibiting XO activity and blocking uric acid production. Five flavonoids and sixteen polypeptides were identified in the phenolic and peptide fractions of MOLH, respectively. MOLH (200 and 500 mg/kg) could effectively reduce the serum UA level of hyperuricemic rats (p < 0.001) by regulation of serum XO activity (p < 0.05 at 200 mg/kg, p < 0.01 at 500 mg/kg) and renal urate transporters. Besides, MOLH could improve metabolic disorders associated with hyperuricemia by its multiple actions on liver MDA (p < 0.001), serum CRE (p < 0.05 at 500 mg/kg) and serum TG (p < 0.001). CONCLUSION: The results provided scientific evidence that MOLH rich in phenolics and peptides ameliorated hyperuricemia and metabolic disorders. This study validated the potential use of MOLH for regulation of hyperuricemia.

Black tea extract and theaflavin derivatives affect the pharmacokinetics of rosuvastatin by modulating organic anion transporting polypeptide (OATP) 2B1 activity.

Theaflavins (TFs) are derived from black tea, an important source of dietary polyphenols. Although the potential interactions between dietary polyphenols and drugs have been demonstrated through in vitro and in vivo studies, little information is available concerning the influence of TFs on drug disposition. Organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in human enterocytes and plays a role in the intestinal absorption of numerous drugs. The current study evaluated the effects of black tea extracts on the pharmacokinetics of rosuvastatin in rats, and investigated the effect of four major TFs (theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate and theaflavin-3,3'-digallate) on the transport activity of OATP2B1. Black tea extracts significantly decreased the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC0 -8 ) of rosuvastatin by 48% and 37%, respectively (p < 0.001 and p < 0.01, respectively). Moreover, OATP2B1-mediated rosuvastatin and estrone-3-sulfate uptake was significantly reduced in the presence of TFs. A kinetic study revealed that the uptake efficiency (in terms of Vmax /Km ) of rosuvastatin was decreased following treatment with TFs. Black tea extracts also reduced OATP2B1-mediated rosuvastatin uptake. These results suggest that black tea reduces the plasma concentrations of rosuvastatin by inhibiting the intestinal OATP2B1-mediated transport of rosuvastatin.

Anti-hyperuricemic effect of Alpinia oxyphylla seed extract by enhancing uric acid excretion in the kidney.

BACKGROUND: Alpinia oxyphylla is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. PURPOSE: We investigated the anti-hyperuricemic effects of Alpinia oxyphylla seed extract (AE), and the underlying mechanisms of action through in vitro and in vivo studies. METHODS: We evaluated levels of uric acid in the serum and urine, the expression of renal urate transport proteins, and levels of inflammatory cytokines in potassium oxonate (PO)-induced hyperuricemic rats. Xanthine oxidase activity was analyzed in vitro, while cellular uric acid uptake was assessed in oocytes expressing the human urate transporter 1 (hURAT1). Moreover, the main components of AE were analyzed using UPLC. RESULTS: In PO-induced hyperuricemic rats, 200 and 400 mg/kg of AE significantly decreased levels of uric acid in serum, while 400 mg/kg of AE increased uric acid levels in urine. AE did not inhibit xanthine oxidase in vitro; however, 1, 10, and 100 µg/ml of AE significantly decreased uric acid uptake into oocytes expressing hURAT1. Furthermore, 400 mg/kg of AE increased levels of organic anion transporter (OAT) 1 protein, while 200 and 400 mg/kg of AE decreased the protein content of urate transporter, URAT1 and inflammatory cytokines in the kidneys. Nootkatone was identified as one the main chemical components in AE from UPLC analysis. CONCLUSIONS: These findings suggest that AE exerts anti-hyperuricemic and uricosuric effects, which are related to the promotion of uric acid excretion via enhanced secretion and inhibition of uric acid reabsorption in the kidneys. Thus, AE may be a potential treatment for hyperuricemia and gout.

Riparoside B and timosaponin J, two steroidal glycosides from Smilax riparia, resist to hyperuricemia based on URAT1 in hyperuricemic mice.

The roots and rhizomes of Smilax riparia (SR), called "Niu-Wei-Cai" in traditional Chinese medicine (TCM), are believed to be effective in treating gout symptoms. However, it is not clear if the active constituents and uricosuric mechanisms of S. riparia support its therapeutic activities. In this study, we isolated two steroidal glycosides named riparoside B and timosaponin J from the total saponins of S. riparia. We then examined if these two compounds were effective in reducing serum uric acid levels in a hyperuricemic mouse model induced by potassium oxonate. We found that the two steroidal glycosides possess potent uricosuric effect in hyperuricemic mice through decreasing renal mURAT1 mainly and inhibiting XOD activity in a certain extent, which contribute to the enhancement of uric acid excretion and attenuate hyperuricemia-induced renal dysfunction. Riparoside B and timosaponin J may have a clinical utility in treating gout and other medical conditions caused by hyperuricemia.

Interaction of silymarin flavonolignans with organic anion-transporting polypeptides.

Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17ß-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17ß-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients.

Botanical-drug interactions: a scientific perspective.

There is a continued predisposition of concurrent use of drugs and botanical products. A general lack of knowledge of the interaction potential together with an under-reporting of botanical use poses a challenge for the health care providers and a safety concern for patients. Botanical-drug interactions increase the patient risk, especially with regard to drugs with a narrow therapeutic index (e.g., warfarin, cyclosporine, and digoxin). Examples of case reports and clinical studies evaluating botanical-drug interactions of commonly used botanicals in the US are presented. The potential pharmacokinetic and pharmacodynamic bases of such interactions are discussed, as well as the challenges associated with the interpretation of the available data and prediction of botanical-drug interactions. Recent FDA experiences with botanical products and interactions including labeling implications as a risk management strategy are highlighted.

The effect of the newly developed angiotensin receptor II antagonist fimasartan on the pharmacokinetics of atorvastatin in relation to OATP1B1 in healthy male volunteers.

OBJECTIVE: Interactions between coadministered drugs may unfavorably affect pharmacokinetics. This study evaluated whether fimasartan, an angiotensin receptor II antagonist, affected the pharmacokinetics of atorvastatin. METHODS: A randomized, open-label, 2-period, 2-sequence, crossover, multiple-dosing study was conducted with 24 healthy male volunteers. Twelve subjects received 80-mg atorvastatin once daily for 7 days; later, they received 80-mg atorvastatin with 240-mg fimasartan for 7 days. Twelve other subjects received the same drugs in the opposite sequence. Blood samples were collected scheduled intervals for 24 hours after the last dosing to determine plasma concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxy atorvastatin acid, and 2-hydroxy atorvastatin lactone. RESULTS: Compared with atorvastatin alone, coadministration of fimasartan and atorvastatin increased the atorvastatin acid mean (95% confidence interval) maximum concentration (Cmax,ss) by 1.89-fold (1.49-2.39) and the area under the concentration curve (AUCτ,ss) by 1.19-fold (0.96-1.48). Fimasartan also increased the mean 2-hydroxy atorvastatin acid Cmax,ss and AUCτ,ss by 2.45-fold (1.80-3.35) and 1.42-fold (1.09-1.85), respectively. The Cmax,ss and AUCτ,ss of the lactone forms of atorvastatin showed smaller changes than those observed for the acidic forms. CONCLUSION: We showed that fimasartan raised plasma atorvastatin concentrations. In vitro tests suggested that this effect may have been mediated by fimasartan inhibition of organic anion-transporting polypeptide 1B1.

Evidence for the plasma membrane localization of Al-activated malate transporter (ALMT1).

Aluminum (Al)-activated malate transporter (ALMT1) was recently identified from wheat (Triticum aestivum). Heterologous expression of ALMT1 led to higher malate exudation that is associated with enhanced Al tolerance in transgenic plants. Here, we show the first direct evidence that ALMT1 is localized in the plasma membrane of Al-tolerant wheat. Phase partitioning experiments showed that this transporter was associated with the plasma membrane fraction. ALMT1 was detected in an Al-tolerant wheat line even without Al treatments. Analysis of transient expression of ALMT1::green fluorescent protein (GFP) in onion and tobacco cells further confirmed this ALMT1 localization.