Studies on Increased Bile Formation Produced by Polyoxybenzenes in Rats

Tanayama, Shigeharu; Kanai, Yoshio

doi:10.1254/jjp.27.71

Cited by 19 publications

(8 citation statements)

References 15 publications

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“…4-MU is already an established therapeutic currently used in humans. Called “hymecromone,” it is used in multiple countries mainly for its choleretic and biliary antispasmodic activity ( 144 – 147 ). Despite being a coumarin derivative, hymecromone does not possess anticoagulant properties.…”

Section: Hymecromonementioning

confidence: 99%

4-Methylumbelliferone Treatment and Hyaluronan Inhibition as a Therapeutic Strategy in Inflammation, Autoimmunity, and Cancer

et al. 2015

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Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. Recent publications have demonstrated that when HA synthesis is inhibited using 4-methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases. Notably, 4-MU is an already approved drug in Europe and Asia called “hymecromone” where it is used to treat biliary spasm. However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition. Here, we review what is known about how HA contributes to immune dysregulation and tumor progression. Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety. Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity.

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Section: Hymecromonementioning

confidence: 99%

4-Methylumbelliferone Treatment and Hyaluronan Inhibition as a Therapeutic Strategy in Inflammation, Autoimmunity, and Cancer

et al. 2015

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“…We have chosen to reexamine 4MU and its conjugates, and we have performed rat liver perfusion experiments aimed at identifying the influence of binding and permeation characteristics on the extent of futile cycling between the drug and its metabolites. 4MU (Hymercromone, 7-hydroxy-4-methylcoumarin) is a choleretic agent (16)(17)(18) whose action is attributed mainly to its glucuronide conjugate (4MUG). Besides glucuronidation, 4MU is also known to form a sulfate conjugate (4MUS) in most animal species (19)(20)(21)(22)(23).…”

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confidence: 99%

Futile cycling between 4-methylumbelliferone and its conjugates in perfused rat liver

et al. 1993

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Futile cycling between 4-methylumbelliferone and its sulfate and glucuronide conjugates was examined in the single-pass perfused rat liver preparation. The steady-state hepatic extraction ratio of 4-methylumbelliferone was found to be high (0.97) at a low input concentration of 0.005 mumol/L (tracer), with a net 4-methylumbelliferyl sulfate/4-methylumbelliferyl glucuronide ratio of about 5:1; at 63 mumol/L the steady-state extraction ratio had remained constant despite a shift from net sulfation to net glucuronidation. At higher input 4-methylumbelliferone concentrations, saturation was evidenced by a decreased steady-state extraction ratio and reduced net sulfation and net glucuronidation. Because 4-methylumbelliferyl sulfate and 4-methylumbelliferyl glucuronide deconjugation would result in an intracellular accumulation of 4-methylumbelliferone, the phenomenon was monitored with a shift in tracer [3H]4-methylumbelliferone metabolism from sulfation to glucuronidation with increased intracellular 4-methylumbelliferone concentration. When 4-methylumbelliferyl sulfate (0 to 890 mumol/L) or 4-methylumbelliferyl glucuronide (0 to 460 mumol/L) was delivered simultaneously with tracer [3H]4-methylumbelliferone to the rat liver, notable desulfation of 4-methylumbelliferyl sulfate (18% to 38% rate in) but little deglucuronidation of 4-methylumbelliferyl glucuronide (1.2% to 2.1% rate in) was observed. With 4-methylumbelliferyl sulfate, 4-methylumbelliferone and 4-methylumbelliferyl glucuronide were readily found as metabolites, whereas with 4-methylumbelliferyl glucuronide, levels of the metabolites, 4-methylumbelliferone and 4-methylumbelliferyl sulfate, were much reduced. 4-Methylumbelliferyl sulfate and not 4-methylumbelliferyl glucuronide shifted tracer [3H]4-methylumbelliferone metabolism from [3H]4-methylumbelliferyl sulfate to [3H]4-methylumbelliferyl glucuronide formation in a concentration-dependent fashion. The steady-state extraction ratio for 4-methylumbelliferyl sulfate (0.1 to 0.3) was comparatively higher than that for 4-methylumbelliferyl glucuronide (0.05), and it was found to increase with concentration, an observation explained by the nonlinear protein binding of 4-methylumbelliferyl sulfate. Biliary excretion rates for 4-methylumbelliferone and 4-methylumbelliferyl sulfate were proportional to their input or net formation rates, regardless of whether 4-methylumbelliferone, 4-methylumbelliferyl glucuronide or 4-methylumbelliferyl sulfate was administered. By contrast, the excretion rate of 4-methylumbelliferyl glucuronide when administered was only 1/25 the excretion of 4-methylumbelliferyl glucuronide formed from 4-methylumbelliferone and 4-methylumbelliferyl sulfate. The extent of choleresis paralleled the excretion patterns of preformed and formed 4-methylumbelliferyl glucuronide; bile flow was normal with 4-methylumbelliferyl glucuronide administration and was markedly enhanced with increased 4-methylumbelliferone or 4-methylumbelliferyl sulfate administration. The data suggest the presence of a tr...

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“…Сочетая в себе спазмолитические и желчегонные свойства, гимекромон обеспечивает опорожнение внутри-и внепеченочных желчных путей, своевременное поступление желчи в двенадцатиперстную кишку (ДПК) [9]. Согласно существующим данным, гимекромон не усиливает синтез желчных кислот [10], что повышает безопасность препарата для пациентов с хроническим панкреатитом (ХП). Препарат облегчает приток желчи в пищеварительный тракт, усиливая энтерогепатическую циркуляцию желчных кислот, которые участвуют в первой фазе образования желчи [11].…”

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Hymecromone Efficacy in the Treatment of Biliary Pancreatitis

Okhlobystin

Татаркина

Охлобыстина

et al. 2019

Rossijskij žurnal gastroènterologii, gepatologii, koloproktolog

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Aim. To study the contribution of biliary sludge (BS) to the development of chronic pancreatitis in patients with gallbladder sludge and verified chronic pancreatitis; to evaluate the clinical efficacy and safety of hymecromone therapy according to clinical and laboratory signs, as well as dynamics of gallbladder size and contractility.Materials and methods. An open single-centre clinical trial included 30 patients with chronic pancreatitis (CP), which was diagnosed according to the Cambridge criteria. All patients received hymocromone (Odeston®) 400 mg tid for 3 weeks. An analysis of the efficacy and safety of the studied drug was performed on the 21st day of treatment based on the results of laboratory tests, abdominal ultrasound, cholecystography and endosonography of the pancreatobiliary zone, quality-of-life assessment according to the SF-36 questionnaire, the frequency and severity of adverse effects (AE).Results. CP signs were found in 6.3 % of patients with gallbladder BS. CP was significantly more frequent in patients with putty-like bile (33.3 %, χ2 = 38.21, p < 0.00001). The area of the major duodenal papilla (MDP) was below normal in 78% of patients. According to factor analysis, monotherapy with hymocromone resulted in a decrease in abdominal pain, nausea, heaviness in the abdomen and bloating. By the end of the therapy, the quality of life according to the “BP” bodily pain scale of the SF-36 questionnaire significantly increased.Conclusions. Biliary sludge (including undiagnosed forms during routine examination) was found to be a factor in the development of CP. The medical correction of biliary disorders in CP should include selective antispasmodics. Hymecromone therapy demonstrates a good level of tolerability and safety, normalizes the motor function of the biliary tract and sphincter tone over a short period of time, and relieves CP symptoms.

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Studies on Increased Bile Formation Produced by Polyoxybenzenes in Rats

Abstract: Abstract-Mechanism of hypercholeretic effect of three polyoxybenzenes,

Cited by 19 publications

References 15 publications

4-Methylumbelliferone Treatment and Hyaluronan Inhibition as a Therapeutic Strategy in Inflammation, Autoimmunity, and Cancer

4-Methylumbelliferone Treatment and Hyaluronan Inhibition as a Therapeutic Strategy in Inflammation, Autoimmunity, and Cancer

Futile cycling between 4-methylumbelliferone and its conjugates in perfused rat liver

Hymecromone Efficacy in the Treatment of Biliary Pancreatitis

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