Absorption, metabolism, and excretion of thiabendazole in man and laboratory animals

doi:10.1016/0041-008X(66)90027-5

Toxicology and Applied Pharmacology

Volume 9, Issue 1, July 1966, Pages 31-39

https://doi.org/10.1016/0041-008X(66)90027-5 Get rights and content

Abstract

After oral administration of 1.0 g of thiabendazole-¹⁴C to man, absorption was rapid and peak plasma concentrations of 13–18 μg/ml were found about 1 hour after treatment. Drug plasma levels declined rapidly and approached essentially zero between 24 and 48 hours. Thiabendazole and its metabolic products were excreted rapidly by the kidney, with 92% of the radioactivity found in the urine (87%) and feces (5%) within 48 hours. The bulk of this appeared in the urine in 24 hours.

Thiabendazole was also rapidly absorbed from the gastrointestinal tract of rats and dogs. In these species, excretion was essentially complete within 3 days.

Approximately one-half of the radioactivity in the urine of man, less in the dog, and considerably more in the rat, was found to be associated with compounds which were identified chemically. These compounds were primarily the glucuronide and sulfate esters of 5-hydroxythiabendazole.

In plasma, and to a small extent in urine, both unchanged thiabendazole and free 5-hydroxythiabendazole were also found.

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Complications in residue studies with radioisotope drugs

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2021, Journal of Hazardous Materials
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First, the parent compound might be transformed back through the WWTP from metabolites or other compounds (Köck-Schulmeyer et al., 2013). Indeed, conjugated metabolites were identified for terbutryn (glutathione conjugated (Jeon et al., 2013)), thiabendazole (glucuronide and sulfate ester of 5-hydroxythiabendazole (Tocco et al., 1966)), and tebuconazole (TEB−OH and TEB−COOH, both as free molecules and as glucuronide conjugates (Mercadante et al., 2014)), which hence supports the first hypothesis for these three substances. For diuron, more investigations are needed to explain the negative removal.
Eighteen biocides used in building materials and domestic products were monitored in wastewater treatment plants (WWTPs) during dry weather and in combined sewer overflows (CSOs) during wet weather in the Paris conurbation. The aims of this study were to (i) acquire data on biocides in urban waters, which are very scarce up to now, (ii) identify their origins in CSOs with the perspective of reducing these contaminants at source, and (iii) compare and rank biocide pathways to the river (dry vs. wet weather) at the annual and conurbation scales. The results showed the ubiquity of the 18-targeted biocides in WWTP waters and CSOs. High concentrations of methylisothiazolinone, benzisothiazolinone (0.2−0.9 μg/L) and benzalkonium C12 (0.5−6 μg/L) were measured in wastewater. Poor WWTP removals (< 50 %) were observed for most of the biocides. Both wastewater (mainly domestic uses) and stormwater (leaching from building materials) contributed to the CSO contamination. However, benzisothiazolinone mainly came from wastewater whereas diuron, isoproturon, terbutryn, carbendazim, tebuconazole, and mecoprop mainly came from stormwater. Annual mass loads discharged by WWTPs and CSOs into the Seine River were estimated using a stochastic approach (Monte Carlo simulations) at the conurbation scale and showed that WWTP discharges are the major entry pathway.
The fungicide thiabendazole causes apoptosis in rat hepatocytes
2016, Toxicology in Vitro
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However, exposure to thiabendazole at higher concentrations exceeding 1000 μM for 10 h caused LDH release in rat hepatocytes, whereas LDH release was not detected at 500 μM (Sugihara et al., 1997). The micromolar concentrations of thiabendazole used in all of these studies are higher than the peak plasma concentrations (13 to 18 μg/ml) detected in humans (Tocco et al., 1966; EMA, 2004). However, hepatocytes were exposed to the drug for relatively short times (24 to 72 h) in these in vitro studies, whereas animals and humans are exposed to lower doses of thiabendazole for prolonged periods of time through diet and environment.
Many pharmaceutical drugs cause hepatotoxicity in humans leading to severe liver diseases, representing a serious public health issue. This study investigates the ability of the anthelmintic and antifungal drug thiabendazole to cause cell death by apoptosis and metabolic changes in primary cultures of rat hepatocytes. Thiabendazole (200–500 μM) induced apoptosis in hepatocytes after 1 to 24 h, causing loss of mitochondrial membrane potential, cytochrome c release from mitochondria, Fas-associated death domain (FADD) translocation from the cytosol to membranes, and activation of caspases-3, -8 and -9. Thus, thiabendazole activated both the mitochondrial and death receptor pathways of apoptosis. Under these conditions, cell death by necrosis was not detected following exposure to thiabendazole (100–500 μM) for 24–48 h, measured by lactate dehydrogenase release and propidium iodide uptake. Furthermore, thiabendazole increased activities of cytochrome P450 (CYP) isoenzymes CYP1A and CYP2B after 24 and 48 h, determined by 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) activities, respectively. An important finding is that thiabendazole can eliminate hepatocytes by apoptosis, which could be a sensitive marker for hepatic damage and cell death. This study improves understanding of the mode of cell death induced by thiabendazole, which is important given that humans and animals are exposed to this compound as a pharmaceutical agent and in an environmental context.
Determination of 5-hydroxythiabendazole in human urine as a biomarker of exposure to thiabendazole using LC/MS/MS
2014, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
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The solubility of TBZ may be the dependent factor. Moreover, metabolites not found by the analytical method are likely to be formed; since the benzene ring in TBZ can undergo ring cleavage and, sulfoxidation has also been suggested [12]. Before the experimental exposure, the 5-OH-TBZ levels in urine were below LOD in both volunteers.
Thiabendazole (TBZ) is widely used as a pre-planting and post-harvest agricultural fungicide and as an anthelminthic in humans and animals. TBZ is of toxicological concern, since adverse effects including nephrogenic, hepatogenic, teratogenic and neurological effects have been reported in mammals. Occupational exposure can occur among agricultural workers and the general public may be environmentally exposed to TBZ through the diet. The metabolite 5-hydroxythiabendazole (5-OH-TBZ) was chosen as biomarker of exposure to TBZ and a LC/MS/MS method for the quantification of 5-OH-TBZ in human urine was developed. The method includes enzyme hydrolysis, as 5-OH-TBZ is conjugated to glucuronide and sulphate in urine. Sample through put was optimised using 96-well plates for sample handling as well as for solid phase extraction (SPE). The method has excellent, within-run, between-run and between-batch precision between 4 and 9%. The limit of detection (LOD) of 0.05 and a limit of quantification (LOQ) of 0.13 ng 5-OH-TBZ/mL urine enable detection in environmentally exposed populations. When applying the method in a general Swedish population, 52% had levels above LOD. The method was also applied in one oral and one dermal human experimental exposure study in two individuals. After oral exposure, the excretion of 5-OH-TBZ in urine was described by a two-compartment model and both the first rapid and the second slower elimination phase followed first-order kinetics, with estimated elimination half-life of 2 h and 9–12 h. The recoveries in urine were between 21 and 24% of the dose. Dermal exposure was described by a one compartment model and followed first order kinetics, with estimated elimination half-life of 9–18 h. The recovery in urine was 1% of the administrated dose of TBZ. Although these studies are limited to two individuals, the data provide new basic information regarding the toxicokinetics of TBZ after oral and dermal exposure.
Myeloperoxidase-mediated bioactivation of 5-hydroxythiabendazole: A possible mechanism of thiabendazole toxicity
2011, Toxicology in Vitro
Citation Excerpt :
Additionally, TBZ is used as an agricultural antifungal and food preservative (Walton et al., 1999). Radiometric assays in humans, conducted by Tocco et al. (1966), have shown that oral dosage of TBZ yields a peak plasma level after 2 h. After 24 h, 85% of the radio-labeled drug has been excreted in urine (61%) or feces (24%).
Thiabendazole (TBZ), an antihelminthic and antifungal agent, is associated with a host of adverse effects including nephrotoxicity, hepatotoxicity, and teratogenicity. Bioactivation of the primary metabolite of TBZ, 5-hydroxythiabendazole, has been proposed to yield a reactive intermediate. Here we show that this reactive intermediate can be catalyzed by myeloperoxidase (MPO), a neutrophil-bourne peroxidase. Using a cell viability endpoint, we examined the toxicity of TBZ, 5OH-TBZ, and MPO-generated metabolites in cell-based models including primary rat proximal tubule epithelial cells, NRK-52E rat proximal tubule cells, and H9C2 rat myocardial cells. Timecourse experiments with MPO showed complete turnover of 5OH-TBZ within 15 min and a dramatic leftward shift in dose–response curves after 12 h. After a 24 h exposure in vitro, the LC₅₀ of this reactive intermediate was 23.3 ± 0.2 μM reduced from greater than 200 μM from 5OH-TBZ alone, an approximately 10-fold decrease. LC₅₀ values were equal in all cell types used. Comparison of lactate dehydrogenase leakage and caspase 3/7 activity revealed that cell death caused by the reactive intermediate is primarily associated with necrosis rather than apoptosis. This toxicity can be completely rescued via incubation with rutin, an inhibitor of MPO. These results suggest that MPO-mediated biotransformation of 5OH-TBZ yields a reactive intermediate which may play a role in TBZ-induced toxicity.
Efficacy of thiabendazole, mebendazole, levamisole and ivermectin against gullet worm, Gongylonema pulchrum: In vitro and in vivo studies
2008, Veterinary Parasitology
In vitro and in vivo studies were conducted to evaluate the effects of thiabendazole, mebendazole, levamisole and ivermectin against Gongylonema pulchrum. For in vitro assays, third-stage larvae (L3) incubated with the drugs were administered orally to mice and the ability of larvae to invade the gastric mucosa of the animals was examined. After incubation, only those larvae treated with high concentrations of levamisole (1 and 10 μg/ml) were tightly coiled with intestines exhibiting morphological abnormalities. Good dose–response data for the drugs tested was observed at the time of worm recovery from mice, with no worms recovered at the two highest concentrations of levamisole. In vivo efficacy of the drugs against adult worms was evaluated in six groups of three rabbits, each of which was infected with 30 L3 of G. pulchrum and treated with thiabendazole at 100 mg/kg for 3 days, mebendazole at 70 mg/kg for 3 days, levamisole as a single dose of 8 mg/kg, and subcutaneously injected ivermectin as a single dose of 0.2 mg/kg or vehicles of the drugs (control) at 4 months post-infection. Necropsy 14 days after treatment revealed that levamisole, mebendazole and ivermectin reduced worm burdens by 63.2%, 22.8% and 25.8%, respectively, with no reductions in worms observed with thiabendazole. The surviving worms were principally found in the esophagus with the remainder distributed among the buccal mucosa, the tongue, and/or pharyngeal mucosa in all groups. A number of morphologically abnormal eggs were observed within the uterus and ovijector in female worms recovered from the thiabendazole-treated group. These findings suggest that levamisole exhibits in vivo efficacy against G. pulchrum infection and that the larval invasion tests using mice could be used to screen for anthelmintic susceptibility of nematodes.
Effect of thiabendazole on some rat hepatic xenobiotic metabolising enzymes
2004, Food and Chemical Toxicology
The effect of thiabendazole (TB) on some rat hepatic xenobiotic metabolising enzymes has been investigated. Male Sprague–Dawley rats were fed control diet or diets containing 102–5188 ppm TB for 28 days. As a positive control for induction of hepatic xenobiotic metabolism, rats were also fed diets containing 1457 and 10,155 ppm butylated hydroxytoluene (BHT). Treatment with TB and BHT resulted in dose-dependent increases in relative liver weight. TB was found to be a mixed inducer of cytochrome P450 (CYP) forms in the CYP1A and CYP2B subfamilies. The administration of high doses of TB resulted in the induction of 7-ethoxyresorufin O-deethylase and 7-pentoxyresorufin O-depentylase activities, CYP1A1, CYP1A2, CYP2B1 and CYP2B1/2 mRNA levels and CYP1A2 and CYP2B1/2 apoprotein levels. In contrast, BHT was a CYP2B form inducer, increasing 7-pentoxyresorufin O-depentylase activity, CYP2B1 and CYP2B1/2 mRNA levels and CYP2B1/2 apoprotein levels. Both TB and BHT induced GSH S-transferase activities towards a range of substrates. In addition, TB and BHT markedly induced GSTP1 mRNA levels, but had only a small effect on GSTT1 mRNA levels. In summary, these results demonstrate that TB induces both phase I and II xenobiotic metabolising enzymes in rat liver.

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Absorption, metabolism, and excretion of thiabendazole in man and laboratory animals

Abstract

J. Invest. Dermatol.

Treatment of trichostrongylosis in human subjects with thiabendazole

O. Hospital (Rio de Janeiro)

Clinical trials with thiabendazole against human strongyloidiasis

Am. J. Trop. Med. Hyg.

Complications in residue studies with radioisotope drugs