Pharmacokinetics of anti-SARS-CoV agent niclosamide and its analogs in rats

Chang, Yi Wei; Yeh, Teng Kuang; Lin, Ke; Chen, Wei Cheng; Yao, Hsien Tsung; Lan, Shih-Jung; Wu, Yu; Hsieh, Hsing Pang; Chen, Chi Min; Chen, Chiung Tong

doi:10.38212/2224-6614.2464

Cited by 32 publications

(34 citation statements)

References 15 publications

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“…Chang et al reported the pharmacokinetic parameters of niclosamide in the rat when administered orally at 5 mg/kg [105] . Niclosamide exhibits a short half-life (6.0 ± 0.8 h).…”

Section: Pharmacokinetic Improvement Of Niclosamide For Treating Systmentioning

confidence: 99%

Niclosamide: Beyond an antihelminthic drug

Chen

Mook

Premont

et al. 2018

Cellular Signalling

325

258

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Niclosamide is an oral antihelminthic drug used to treat parasitic infections in millions of people worldwide. However recent studies have indicated that niclosamide may have broad clinical applications for the treatment of diseases other than those caused by parasites. These diseases and symptoms may include cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, and systemic sclerosis. Among the underlying mechanisms associated with the drug actions of niclosamide are uncoupling of oxidative phosphorylation, and modulation of Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways. Here we provide a brief overview of the biological activities of niclosamide, its potential clinical applications, and its challenges for use as a new therapy for systemic diseases.

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“…Chang et al reported the pharmacokinetic parameters of niclosamide in the rat when administered orally at 5 mg/kg [105] . Niclosamide exhibits a short half-life (6.0 ± 0.8 h).…”

Section: Pharmacokinetic Improvement Of Niclosamide For Treating Systmentioning

confidence: 99%

Niclosamide: Beyond an antihelminthic drug

Chen

Mook

Premont

et al. 2018

Cellular Signalling

325

258

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“…The therapeutic effects were reported to be via the uncoupling of the electron transport chain from the adenosine triphosphate synthase, resulting in blockage of the synthesis of adenosine triphosphate, which is an essential source of energy for cellular metabolism (Al-Hadiya, 2005). Recently, niclosamide has emerged as a strong candidate for drug repurposing and repositioning, as this antiparasitic drug has been shown to have therapeutic effects against viruses, inflammation, and cancer, and can also regulate glucose metabolism in obese subjects (Chang et al, 2006;Piccaro et al, 2013;Li et al, 2014;Chowdhury et al, 2017). Niclosamide is in clinical trials for treating colon cancer and prostate cancer (Clinicaltrials.gov Identifier, NCT02532114; NCT03123978; NCT02687009).…”

Section: Introductionmentioning

confidence: 99%

Contributions of Hepatic and Intestinal Metabolism to the Disposition of Niclosamide, a Repurposed Drug with Poor Bioavailability

Fan

Ding

et al. 2019

Drug Metab Dispos

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Niclosamide, an antiparasitic, has been repositioned as a potential therapeutic drug for systemic diseases based on its antiviral, anticancer, and anti-infection properties. However, low bioavailability limits its in vivo efficacy. Our aim was to determine whether metabolic disposition by microsomal P450 enzymes in liver and intestine influences niclosamide's bioavailability in vivo, by comparing niclosamide metabolism in wild-type, liver-Cpr-null (LCN), and intestinal epithelium-Cpr-null (IECN) mice. In vitro stability of niclosamide in microsomal incubations was greater in the intestine than in liver in the presence of NADPH, but it was much greater in liver than in intestine in the presence of UDPGA. NADPH-dependent niclosamide metabolism and hydroxy-niclosamide formation were inhibited in hepatic microsomes of LCN mice, but not IECN mice, compared with wild-type mice. In intestinal microsomal reactions, hydroxy-niclosamide formation was not detected, but rates of niclosamide-glucuronide formation were ∼10-fold greater than in liver, in wild-type, LCN, and IECN mice. Apparent Km and V max values for microsomal niclosamide-glucuronide formation showed large differences between the two tissues, with the intestine having higher Km (0.47 mM) and higher V max (15.8) than the liver (0.09 mM and 0.75, respectively). In vivo studies in LCN mice confirmed the essential role of hepatic P450 in hydroxy-niclosamide formation; however, pharmacokinetic profiles of oral niclosamide were only minimally changed in LCN mice, compared with wild-type mice, and the changes seem to reflect the compensatory increase in hepatic UDP-glucuronosyltransferase activity. SIGNIFICANCE STATEMENT These results suggest that efforts to increase the bioavailability of niclosamide by blocking its metabolism by P450 enzymes will unlikely be fruitful. In contrast, inhibition of niclosamide glucuronidation in both liver and intestine may prove effective for increasing niclosamide's bioavailability, thereby making it practical to repurpose this drug for treating systemic diseases.

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“…We next explored pharmacokinetics profiles in Sprague Dawley rats following oral and IV administration of four of these compounds that had previously exhibited good microsomal stability. In a previous study, a 5mg/kg oral dose of niclosamide in rats leads to a peak plasma concentration (Cmax) of 354ng/ml and half-life of 6.7 hours [ 45 ]. Three of the four phenylbenzamide derivatives had significantly improved oral bioavailability compared to niclosamide.…”

Section: Resultsmentioning

confidence: 99%

N-substituted phenylbenzamides of the niclosamide chemotype attenuate obesity related changes in high fat diet fed mice

et al. 2018

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Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient’s progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of steatosis, inflammation and hepatocyte injury with fibrosis. Unfortunately, there are no approved therapies for NAFLD or NASH and therefore therapeutic approaches are urgently needed. Niclosamide is an U.S. Food and Drug Administration (FDA)-approved anthelmintic drug that mediates its effect by uncoupling oxidative phosphorylation. Niclosamide and its salt forms, Niclosamide Ethanolamine (NEN), and Niclosamide Piperazine (NPP) have shown efficacy in murine models of diet induced obesity characterized by attenuation of the prominent fatty liver disease phenotype and improved glucose metabolism. While the exact mechanism(s) underlying these changes remains unclear, the ability to uncouple oxidative phosphorylation leading to increased energy expenditure and lipid metabolism or attenuation of PKA mediated glucagon signaling in the liver have been proposed. Unfortunately, niclosamide has very poor water solubility, leading to low oral bioavailability. This, in addition to mitochondrial uncoupling activity and potential genotoxicity have reduced enthusiasm for its clinical use. More recently, salt forms of niclosamide, NEN and NPP, have demonstrated improved oral bioavailability while retaining activity. This suggests that development of safer more effective niclosamide derivatives for the treatment of NAFLD and Type 2 Diabetes may be possible. Herein we explored the ability of a series of N-substituted phenylbenzamide derivatives of the niclosamide salicylanilide chemotype to attenuate hepatic steatosis using a novel phenotypic in vitro model of fatty liver and the high fat diet-fed mouse model of diet induced obesity. These studies identified novel compounds with improved pre-clinical properties that attenuate hepatic steatosis in vitro and in vivo. These compounds with improved drug properties may be useful in alleviating symptoms and protection against disease progression in patients with metabolic syndrome and NAFLD.

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Pharmacokinetics of anti-SARS-CoV agent niclosamide and its analogs in rats

Cited by 32 publications

References 15 publications

Niclosamide: Beyond an antihelminthic drug

Niclosamide: Beyond an antihelminthic drug

Contributions of Hepatic and Intestinal Metabolism to the Disposition of Niclosamide, a Repurposed Drug with Poor Bioavailability

N-substituted phenylbenzamides of the niclosamide chemotype attenuate obesity related changes in high fat diet fed mice

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