Presence Of Methimazole Research Articles

The Comparison of Catalytic Activity of Carbimazole and Methimazole on Electroreduction of Zinc (II) in Chlorates (VII): Experimental and Molecular Modelling Study.

With the help of electrochemical methods, including CV and EIS, the influence of methimazole, carbimazole, and the concentration of the supporting electrolyte on the kinetics and mechanism of zinc electroreduction on a mercury electrode was compared and analyzed. Moreover, molecular dynamics simulations of zinc/carbimazole and zinc/methimazole solutions were carried out to determine the effect of drugs on the hydration sphere of Zn2+ ions. It was shown that the electroreduction of Zn2+ in the presence of methimazole and carbimazole occurs in two steps and the first one determines the kinetics of the entire process. The presence of both drugs in the solution and the increase in the concentration of the supporting electrolyte reduce the degree of hydration of the depolarizer ions and the hydration of the electrode surface, what is a factor favoring the rate of electroreduction. Based on theoretical studies, the formation of stable complexes between Zn2+ and the molecules of both drugs in a solution was considered unlikely. However, active complexes can be formed between depolarizer ions and molecules adsorbed at the electrode surface. They constitute a bridge facilitating charge exchange during the electrode reaction, revealing the catalytic abilities of methimazole and carbimazole. In the range of cdrug ≤ 1 × 10-3 mol dm-3, carbimazole is a better catalyst, whereas in the range of cdrug ≥ 5 × 10-3 mol dm-3, it is methimazole. The effectiveness of both compounds in catalyzing the first stage of the electrode reaction increases with the increase in the NaClO4 concentration.

The Effect of Supporting Electrolyte Concentration on Zinc Electrodeposition Kinetics from Methimazole Solutions

AbstractThe kinetic parameters of Zn2+ ion electroreduction in sodium perchlorate used as the supporting electrolyte on the mercury electrode in the presence of methimazole were determined using electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and DC polarography. The two‐stage nature of this process was demonstrated. Both steps are catalysed by a methimazole. The size of the acceleration effect depends on the concentrations of methimazole and the supporting electrolyte. The acceleration of the electrode process involves the formation of active complexes between the depolarizer ions and methimazole on the electrode surface. These complexes facilitate the exchange of charge between the electrode and zinc ions during electroreduction process. The change of the hydrating sphere of the zinc ion is also important here. This in turn depends on its oxidation state and the concentration of the supporting electrolyte.

Electrochemical Oxidation of Catechol in the Presence of Methimazole: Application of Square-Wave Voltammetric Detection of Methimazole to Pharmaceutical Formulations

Electrochemical Oxidation of Catechol in the Presence of Methimazole: Application of Square-Wave Voltammetric Detection of Methimazole to Pharmaceutical Formulations

Assessment of liver slices for research on metabolic drug–drug interactions in cattle

1. Precision-cut liver slices (PCLS) from food-producing animals have not been extensively used to study xenobiotic metabolism, and thus information on this field of research is sparse.2. The aims of the present work were to further validate the technique of production and culture of bovine PCLS and to characterize the metabolic interaction between the anthelmintic albendazole (ABZ) and the flavin-monooxygenase (FMO) inhibitor methimazole (MTZ).3. Nine steers were used as donors. PCLS were produced and incubated under two methods: a dynamic organ culture (DOC) incubator and a well-plate (WP) system.4. Tissue viability, assessed through both structural and functional markers, was preserved throughout 12 h of incubation. ABZ was metabolized to its (+) and (-) albendazole sulfoxide stereoisomers (ABZSO) in bovine PCLS. The interaction between ABZ and MTZ resulted in a reduction (p < 0.001) in the rates of appearance of (+) ABZSO. Conversely, in presence of MTZ, the rates of appearance of (−) ABZSO increased under both systems (p < 0.05).5. Both culture systems were suitable for assessing the interaction between ABZ and MTZ.6. Overall, the results presented herein show that PCLS are a useful and reliable tool for short-term studies on metabolic drug–drug interactions in the bovine species.

Methimazole-disulfide as an Anti-Thyroid Drug Metabolite Catalyzed the Highly Regioselective Conversion of Epoxides to Halohydrins with Elemental Halogens

The regioselective ring opening of epoxides using elemental iodine and bromine in the presence of methimazole (MMI, a anti-thyroid drug) and its metabolite methimazole-disulfide as new catalysts are studied. MMI easily converted in vitro to MMI-disulfide without any double activation presented in vivo. FT-Raman and UV spectroscopies are used to study the interaction of iodine with these catalysts. The results indicate that both catalysts are efficient in polyiodide formation, but MMI-disulfide can catalyze this reaction in higher yield and regioselectivity. The complex [(MMI-disulfide)I]+.I3- is considered to be formed initially which could be bulkier by addition of excess of iodine in the course of the reaction. These bulky nucleophiles have a fundamental role in the high regioselectivity by attacking the less sterically hindered epoxide carbon. In this study we suggest that MMI is readily converted to MMI-disulfide by interaction with iodine or activated iodine in thyroid gland, and this process is responsible for high anti-thyroid activity of MMI.

S-oxidation of S-methyl-esonarimod by flavin-containing monooxygenases in human liver microsomes

1. Studies using human liver microsomes and recombinant human cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) were performed to identify the enzymes responsible for the metabolism of S-methyl-esonarimod (M2), an active metabolite of esonarimod (KE-298, a novel antirheumatic drug).2. S-oxidative activities of M2 significantly correlated with those of methyl p-tolyl sulfide, a specific substrate of FMOs, as tested using 10 different human liver microsomes (r2 = 0.539, p<0.05). Thermal treatment of microsomes reduced the S-oxidative activity in the absence of the NADPH-generating system at 45°C for 5 min. However, methimazole, a known competitive substrate of FMOs, was a weak inhibitor of the S-oxidation in liver microsomes.3. Recombinant human FMO1 and FMO5 produced M3 in greater quantities than recombinant human FMO3. The S-oxidation of M2 by recombinant human FMO5 was not appreciably inhibited in the presence of methimazole. In contrast, methimazole was effective in suppressing the catalytic activity of recombinant human FMO1 and FMO3.4. The apparent Km (Km app) for the S-oxidation of M2 in human recombinant FMO5 (2.71 μM) was similar to that obtained using human liver microsomes (2.43 μM).5. The present results suggest that the S-oxidation of S-methyl esonarimod reflects FMO5 activity in the human liver because the recombinant FMO5 data match well with the human liver microsomal experiments.

Liver sulphoxidative metabolism of albendazole in rat: enantioselectivity and effect of methimazole.

The aim of the present work was to evaluate the effects of methimazole (MTZ) on the enantioselective sulphoxidation of albendazole (ABZ) by rat liver microsomes and tissue slices. Albendazole sulphoxide (ABZSO) was the metabolite recovered after the incubation with ABZ in both liver preparations. MTZ significantly reduced ABZSO production both in microsomes and slices. ABZSO production decreased as a function of MTZ concentration. The sulphoxidation reaction performed by rat liver explants in the presence of MTZ was 65% lower than that observed in controls. The reduction in the production of ABZSO in the presence of MTZ was mainly due to a lower production of (+) ABZSO. The results reported further contribute to the understanding of the enantioselective metabolism of ABZ. In addition, the work presented provides information on the comparison of two different liver tissue preparations for the evaluation of xenobiotic metabolism.

Oxidation of Caffeine to Theobromine and Theophylline Is Catalyzed Primarily by Flavin-Containing Monooxygenase in Liver Microsomes

Upon N-demethylation of caffeine (CA) by rat and human liver microsomes, theobromine (TB), paraxanthine (PX), and theophylline (TP) are produced. The optimal pHs for the formation of TB, PX, and TP from CA by rat liver microsomes are 7.4 (most), 8.2 (minor) and 8.6 (moderate). At pH 7.4, PX is the primary metabolite formed and makes up 48 % of the CA metabolites generated. In the presence of SKF525A, an inhibitor of P450 (CYP), the rates of TB, PX and TP production are inhibited by 32 %, 68 % and 42 %, respectively. Alternatively, in the presence of methimazole, an inhibitor of flavin-containing monooxygenase (FMO), the rates of TB, PX and TP production are inhibited by 66 %, 48 % and 73 %, respectively. In the presence of both SKF525A and methimazole, they are inhibited by 95 %, 84 % and 94 %, respectively. With human liver microsomes, the CA is metabolized faster but is inhibited more extensively either by SKF525A (PX production) or by methimazole (TB production). Alternatively, when CA is metabolized at pH 8.6, the optimal pH of FMO catalyzed reaction, the rates of TB and TP formation are increased but the rate of PX production is decreased. Furthermore, at pH 8.6 and in the presence of methimazole, the rates of TB and TP formation are decreased by 82 % and 95 %, respectively. These results indicate that the FMO is responsible primarily for productions of TB and TP and the CYP for PX.

Olfactory toxicity of methimazole: dose-response and structure-activity studies and characterization of flavin-containing monooxygenase activity in the Long-Evans rat olfactory mucosa.

Methimazole is a compound administered to humans for the treatment of hyperthyroidism and is used experimentally as a model substrate for the flavin-containing monooxygenase (FMO) system. Previous results from this laboratory demonstrated that methimazole is an olfactory system toxicant, causing nearly complete destruction of the olfactory epithelium in the male Long-Evans rat following a single ip dose of 300 mg/kg. The present studies were undertaken to determine the dose-response relationship for methimazole-induced olfactory mucosal damage and to determine whether or not similar damage occurs as a result of oral administration, mimicking the relevant route of human exposure. We also investigated the mechanism of olfactory toxicity of methimazole by means of a structure-activity study and began the characterization of the form(s) of FMO present in the olfactory mucosa of the male Long-Evans rat. Dose-response analysis demonstrated that methimazole causes olfactory mucosal damage at doses of 25 mg/kg ip and greater. The results of gavage studies showed that a single oral dose of 50 mg/kg also caused olfactory mucosal damage. Two structurally related compounds, methylimidazole and methylpyrrole, were not olfactory toxicants, suggesting that a reactive intermediate generated in the course of metabolizing methimazole to an S-oxide is the olfactory toxic species. Microsomal incubation studies revealed the presence of methimazole S-oxidation activity in olfactory mucosal microsomes at levels comparable to those in liver. An anti-mouse liver FMO antibody reacted on Western blots with olfactory mucosal microsomes. These findings demonstrate a dose-response for the olfactory toxicity of methimazole and suggest that characterization of human olfactory mucosal FMO activity may be necessary to assess the potential for human risk associated with therapeutic exposure to methimazole.

Bioactivation mechanism of S-(3-oxopropyl)-N-acetyl-L-cysteine, the mercapturic acid of acrolein.

S-(3-Oxopropyl)glutathione, the glutathione conjugate of acrolein, has been reported to be nephrotoxic. The objective of the present studies was to investigate the bioactivation mechanism of the analogues S-(3-oxopropyl)-N-acetyl-L-cysteine (1) and S-(3-oxopropyl)-N-acetyl-L-cysteine S-oxide (2) and to test the hypothesis that the cytotoxicity of 1 is associated with its latent potential to release acrolein in kidney cells. Mechanistic considerations indicated that sulfoxidation of sulfide 1 to form S-oxide 2 and a subsequent general-base-catalyzed beta-elimination reaction would release the cytotoxin acrolein. Hence the release of acrolein from 1 and 2 was studied in chemical systems, and their cytotoxicity was investigated in cultured LLC-PK1 cells and in isolated rat renal proximal tubular cells. Acrolein formation from S-oxide 2, but not from sulfide 1, was observed under basic conditions and with phosphate as the base. Kinetic analysis indicated that a general-base-catalyzed reaction was involved. Both S-conjugates 1 and 2 were cytotoxic in LLC-PK1 cells and in isolated rat renal proximal tubular cells, and the cytotoxicity of sulfide 1, but not of S-oxide 2, in isolated renal proximal tubular cells was reduced in presence of methimazole, an inhibitor of the flavin-containing monooxygenase. These findings indicate that the cytotoxicity of S-conjugate 1 is associated with a novel bioactivation mechanism that involves sulfoxidation followed by a general-base-catalyzed elimination of acrolein from S-oxide 2.

Methimazole increases the plasma concentrations of the albendazole metabolites of netobimin in sheep.

The influence of methimazole (MTZ) on the pharmacokinetics of netobimin (NTB) and its metabolites was investigated in adult sheep. NTB zwitterion suspension was administered at 20 mg kg-1 by intraruminal injection either alone or with simultaneous administration of MTZ intramuscularly at 1.5 mg kg-1. Blood samples were taken serially over a 120-h period and plasma was analysed by HPLC for NTB, albendazole (ABZ), albendazole sulphoxide (ABZSO), and albendazole sulphone (ABZSO2). NTB parent drug showed fast absorption, low area under the plasma concentration-time curve (AUC) and was rapidly removed from plasma after both treatments. The presence of MTZ did increase significantly the ABZ AUC (138 per cent) and mean residence time (MRT) (86 per cent). Concomitant treatment with MTZ resulted in a notably higher ABZSO plasma profile with significantly longer elimination half-life (t1/2 beta) (390 per cent) and MRT (252 per cent) and with significantly higher AUC (95 per cent). Also, MTZ induced significant increases in ABZSO2 t1/2 beta, AUC, and MRT. We have demonstrated a pharmacokinetic interaction between MTZ and NTB metabolites. MTZ may alter the liver biotransformation of ABZ metabolites which results in pronounced changes in the disposition kinetics of anthelmintically active metabolites.

Determination of Carbimazole and Methimazole by First and Third Derivative Spectrophotometry

Abstract A rapid method for simultaneous determination of both carbimazole and methimazole by third derivative spectrophotometry is presented. First derivative spectrophotometry is also applied for selective determination of carbimazole in the presence of methimazole. By measuring the absolute values of the first (for carbimazole) and third derivative curves for the mixture, the concentration of each component can be calculated directly without interference from the other. The method was proved using prepared mixtures of the two drugs. The mean accuracies for the determination of carbimazole by first and third derivative spectrophotometry were found to be 100.02 ± 0.29, 100.07 ± 0.17, respectively and 99.97 ± 0.09 for methimazole by third derivative spectrophotometry. The proposed procedures were successfully applied for the analysis of carbimazole in tablet form and its validity was further checked using the standard addition technique.

Postlabeling analysis of carcinogen-DNA adducts in mussel, Mytilus galloprovincialis

The 32P-postlabeling analysis of DNA adducts formed in mussel digestive gland homogenates incubated with 2-aminofluorene (32 μ m) showed one major and one minor adduct in the range of 1 adduct per 1–4 × 10 8 nucleotides. The predominant adduct was found to be chromatographically similar to the known C8-aminofluorene-substituted guanine adduct. The metabolic activation of 2-aminofluorene was blocked in the presence of methimazole (470 μ m), a competitive inhibitor of FAD-containing monooxygenase. In contrast to 2-aminofluorene, benzo( a)pyrene-modified DNA either did not show any adduct or a very weak adduct spot (1 adduct per 1–4 × 10 9 nucleotides). The samples of DNA from mussel, carp and bream, which had no obvious exposure to pollutants, showed one to several weak ‘natural adducts’. The origin of these adducts is as yet undetermined. Since postlabeling assay enables measurement of carcinogen-DNA adducts formed with any, even unknown, chemicals from the composite environmental mixture of genotoxic pollutants, it may become a valuable tool for risk assessment also in marine environments.

Effects of methimazole on human lymphocyte proliferation and natural killer cell activity

1. 1. Methimazole (MM), an antithyroid drug, was examined for its ability to modulate immune functions. The increase in [ 3H]thymidine incorporation in plant mitogen-stimulated lymphocytes and augmentation of NK cell activity by MM were used as a measure of the immunomodulatory activity of MM. 2. 2. The results demonstrated that lymphocytes from 5 different donors had a mean increase of 632% of [ 3H]thymidine incorporation in the presence of MM at a concentration of 114.2 μg/ml ( P < 0.005). 3. 3. Lymphocyte response to PHA, Con A or PWM was potentiated by 27 to 482% in the presence of MM. 4. 4. The MM mediated increase in lymphocyte proliferation was more obvious in cases where the mitogenic stimulation was low. 5. 5. Lymphocyte cytotoxicity to both K562 cells and malignant B cells was also augmented when lymphocytes were cultured in the presence of MM. 6. 6. A maximal effect was observed when lymphocytes were treated with a concentration of 20 μg/ml of MM for 12–16 hr. 7. 7. Maximum augmentation was usually exerted when the NK cell activity of cultured lymphocytes was low. 8. 8. This was particularly seen with lymphocyte from cultured B cell leukemia (3163).

Inhibition by Iodide of the Cholinergic Stimulation of Prostaglandin Synthesis in Dog Thyroid*

Iodide is shown to inhibit the cholinergic stimulation of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha) synthesis in dog thyroid slices. The inibitory effect of iodide was already detectable at 1 micron and reached its maximal level at 10 microns. At this concentration, iodide inhibited the carbamylcholine-stimulated release of PGE2 and PGF2 alpha by 59% and 73%, respectively (eight experiments). The effect of iodide was neither immediate nor rapidly reversed after a change of incubation medium. The unstimulated release of PGE2 and PGF2 alpha and the stimulation by epinephrine and ionophore A23187 were not modified by iodide in concentrations up to 0.1 mM. The effect of iodide was suppressed in the presence of methimazole (0.1 mM) but not NaClO4 (2 mM). Iodid (0.1 mM) did not inhibit the stimulation by carbamylcholine of PGF2 alpha and PGE2 release by rat pancreas in vitro. These data demonstrate a new action of iodide on the thyroid and establish a link among iodide metabolism, PG synthesis, and cholinergic action in the dog thyroid.

Metabolism of thyroid hormones by rat thyroid tissue in vitro.

Rat thyroid lobes or hemilobes have been incubated in Krebs-Ringer phosphate buffer containing labeled T4 and/or T3, and the products were separated by paper chromatography. Labeled T4 was actively degraded; about half of the T4 metabolized was recovered as T3. Labeled T3 was also metabolized, but less rapidly than T4. Other than T3 produced from T4, the major products from both hormones were inorganic iodide and iodoprotein; the latter was presumably a secondary product of iodide organification because its formation was inhibited by hypoxia and methimazole. Feeding the animals a low iodine diet increased their hormone-metabolizing activity. Incubation under nitrogen did not affect the rate of T4 degradation, but partially inhibited T3 degradation. Degradation of both hormones was unchanged in the presence of methimazole and ascorbate, was markedly inhibited by 1 mM propylthiouracil (PTU), and was partially inhibited by azide and cyanide. Thyroid tissues concentrated both hormones, tissue to medium gradients averaging 5.4 for T4 and 20.7 for T3; none of the conditions affecting hormone degradation (incubation under nitrogen or with azide, cyanide, or PTU) significantly altered these gradients. It is concluded that the thyroid can metabolize both of its major hormones by a system distinct from thyroidal peroxidase. Hormone metabolism, therefore, is a potentially important factor in net hormone secretion. In its resistance to hypoxia, methimazole, and ascorbate and its sensitivity to PTU, the thyroid's system for generating T3 from T4 resembles T3-forming systems of liver and kidney. The thyroid, because T3 formation is its dominant pathway for T4 metabolism, may provide a useful model for study of this reaction.

Effects of iodide on thyroid stimulation.

ABSTRACT Iodide directly inhibits thyrotropin (TSH)- or long-acting thyroid stimulator (LATS)-stimulated thyroid hormone release. To investigate the mechanism (s) of iodide inhibition we studied the effects of iodide on adenyl cyclase activation, colloid droplet formation and glucose-1-14C oxidation in sheep thyroid in vitro. Nal alone, 10−5 to 10−3m, consistently stimulated adenyl cyclase, had a marginal stimulatory effect on glucose oxidation, but did not augment colloid droplet formation. The stimulatory effects of TSH and prostaglandin E1 (PGE1) on adenyl cyclase and glucose oxidation and of dibutyryl cyclic-AMP (DBC) on glucose oxidation were inhibited by excess iodide but TSH, PGE1 and DBC stimulation of colloid droplet formation was unaffected. The stimulatory and inhibitory effects of Nal on adenyl cyclase activation and slice metabolism were abolished in the presence of methimazole, 10−4m, in the incubation medium. Twenty-four hr of KI pretreatment markedly inhibited the effects of TSH, LATS, PGE...

Iodine metabolism in surviving thyroid slices from patients with exophthalmic goiter.

Surviving slices of hyperplastic thyroid tissue from 18 patients with exophthalmic goiter prepared for operation with strong iodine solution (Lugol's solution), and of normal thyroid tissue from 4 euthyroid patients were incubated with a solution of Krebs-Henseleit bicarbonate medium and radioiodine by a gravity-flow method. Iodine metabolism in the hyperplastic tissue differed from that of normal tissue in three respects: 1) the pattern of I131 uptake in hyperplastic tissue was curvilinear with respect to time, whereas that of normal tissue was rectilinear; 2) iodine transport was greater in hyperplastic tissue than in normal tissue; and 3) the mean proportion of I131 bound to protein was less in hyperplastic tissue than in normal tissue. In both hyperplastic and normal tissue, binding of I131 to protein was blocked by 10−3 M methimazole (Tapazole). In the presence of methimazole, the accumulated radioiodine was discharged, but not completely, by 0.2 M thiocyanate. Thyroid-to-medium ratios of less than u...