Extrapolating In Vitro Screening Assay Data for Thyroperoxidase Inhibition to Predict Serum Thyroid Hormones in the Rat.

Thyroperoxidase (TPO) is an enzyme essential for thyroid hormone (TH) synthesis and a target site for a number of xenobiotics that disrupt TH homeostasis. An in vitro high-throughput screening assay for TPO inhibition, the Amplex UltraRed-TPO (AUR-TPO), has been used to screen the ToxCast chemical libraries for this action. Output from this assay would be most useful if it could be readily translated into an in vivo response, namely a reduction of TH in serum. To this end, the relationship between TPO inhibition in vitro and serum TH decreases was examined in rats exposed to 2 classic TPO inhibitors, propylthiouracil (PTU) and methimazole (MMI). Serum and gland PTU, MMI, and TH levels were quantified using tandem liquid chromatography mass spectrometry. Thyroperoxidase activity was determined in thyroid gland microsomes treated with PTU or MMI in vitro and ex vivo from thyroid gland microsomes prepared from exposed animals. A quantitative model was constructed by contrasting in vitro and ex vivo AUR-TPO results and the in vivo time-course and dose-response analysis. In vitro:ex vivo correlations of AUR-TPO outputs indicated that less than 30% inhibition of TPO in vitro was sufficient to reduce serum T4 by 20%, a degree of regulatory significance. Although further testing of model estimates using other TPO inhibitors is essential for verification of these initial findings, the results of this study provide a means to translate in vitro screening assay results into predictions of in vivo serum T4 changes to inform risk assessment.

Determination of methimazole based on electropolymerized-molecularly imprinted polypyrrole modified pencil graphite sensor.

Preparation of a molecularly imprinted polymer (MIP) film and its recognition property for methimazole (MMZ) was investigated. The polypyrrole (PPy) film was prepared by the cyclic voltammetric deposition of pyrrole in the presence of a supporting electrolyte (NaClO4·H2O) with and without MMZ through on a pencil graphite electrode (PGE). A computational study based on density functional theory was developed to evaluate the template-monomer geometry and interaction energy in the prepolymerization mixture. The performance of MIP sensor and non-imprinted polymer (NIP) film was evaluated by differential pulse voltammetry (DPV). The most important parameters controlling the performance of sensor were investigated and optimized. The prepared electrode was used for MMZ measurement by a three-step procedure, including analyte extraction in the electrode, electrode washing and electrochemical measurement of MMZ. The molecularly imprinted film exhibited a high selectivity and sensitivity toward methimazole in the experimental conditions. The calibration curve demonstrated linearity over a concentration range of 0.007-6mM with a correlation coefficient (r2) of 0.9808. The accuracy of the method was studied through spiking blank samples showed recovery of 98% with precision of 4%. Limit of detection based on S/N=3 was obtained 3×10-6M. The proposed sensor was applied successfully to determine MMZ in biological model samples and pharmaceuticals.

Sensitive amperometric determination of methimazole based on the electrocatalytic effect of rutin/multi-walled carbon nanotube film.

Electrochemical deposition was used to prepare a glassy carbon electrode modified with multi-walled carbon nanotubes and the glycosidic compound, rutin (R/MWCNTs/GCE). Cyclic voltammetry of the modified electrode in aqueous solution (pH8) showed a pair of well-defined, stable and reversible redox peaks with surface confined characteristics. The catechol moiety of rutin produced the voltammetric peaks via a 2 electron, 2 proton mechanism in the range of 0.0-0.4V (vs. Ag/AgCl). The transfer coefficient (α), heterogeneous electron transfer rate constant (ks), and surface concentration (Γ) for R/MWCNTs/GCE were calculated by using the cyclic voltammetric data. The modified electrode showed excellent catalytic activity toward oxidation of methimazole. Fixed-potential amperometry was used for sub-micromolar determination of methimazole at pH8. Linear dependence of anodic current to methimazole concentration was obtained in the range of 0.1-26µM of the drug with a limit of detection at 18nM. The modified electrode retained its initial response for at least 2weeks if stored in dry ambient conditions. The electrode was used for the amperometric determination of methimazole in formulations and spiked blood serum samples, successfully.

A method for the determination of total and reduced methimazole in various biological samples.

A simple, rapid, reproducible and sensitive method based on HPLC with ultraviolet detection was developed for the determination of methimazole (MMI) in animal tissues and plasma samples. Under the optimum experimental conditions, the calibration curves for MMI were linear in the tested range 0.5-20 mg kg(-1) tissue sample (mg l(-1) plasma) with correlation coefficients better than 0.99. The performance of the proposed method was tested for the determination of MMI levels in brain, liver, thyroid gland and plasma of MMI-treated hens, as well as in their eggs and embryos. The proposed method reduces time and simplifies the sample preparation procedure.

Toxicities associated with 1-month treatment with propylthiouracil (PTU) and methimazole (MMI) in male rats.

Thionamides such as propylthiouracil (PTU) and methimazole (MMI) have been used for more than 50 years to treat the more common causes of thyrotoxicosis/hyperthyroidism such as Graves' disease. Serious adverse effects associated with thionamides in humans include idiosyncratic liver damage, agranulocytosis, aplastic anemia, and vasculitis. Both prospective and retrospective clinical studies with these drugs have failed to identify predictive biomarker for these adverse effects. To assess whether rat is a good model for predicting drug-related adverse events in the liver and in the bone marrow, we conducted a comprehensive study in male rats with multiple doses of PTU and MMI. As expected, euthyroid animals became hypothyroid along with several secondary changes associated with hypothyroidism. There were slight reductions in red blood cell parameters along with some marginal effects on the bone marrow elements. However, there was no evidence of significant neutropenia and liver injury in both PTU-treated and MMI-treated cohorts. MMI-related effects were noted in the seminiferous tubules of the testes. Overall, 1-month daily treatment of euthyroid rats with PTU or MMI resulted in hypothyroidism, minor bone marrow effects, and several secondary effects associated with hypothyroidism, but without any evidence of adverse effects reported in humans including liver injury and agranulocytosis.

The pharmacokinetics of methimazole in a novel lipophilic formulation administered transdermally to healthy cats.

AIM: To determine the pharmacokinetics of a novel lipophilic formulation of transdermal methimazole compared to oral carbimazole. METHODS: Healthy cats received 5 mg carbimazole orally every 12 hours for 13 treatments (n=6), then received transdermal methimazole (n=5) at a dose of 5 mg, then 10 mg, once daily on the pinna for 7 days, with 21 days between treatments. Concentrations of methimazole in serum over 24 hours and at 148 hours were determined by high performance liquid chromatography. RESULTS: Concentrations of methimazole in serum for the first 24 hours were not reliably detected in all cats treated with 5 mg methimazole transdermally, while for those receiving 5 mg carbimazole orally and 10 mg methimazole transdermally all cats had detectable concentrations of methimazole in serum. The maximum concentration and area under the curve were lower in cats receiving 10 mg methimazole transdermally (108 (SD 25) ng/mL and 2544 (SD 216) mg-hour/mL, respectively) than those receiving 5 mg oral carbimazole (355 (SD 113) ng/mL and 31,866 (SD 439) ng-hour/mL, respectively) (p<0.05). The time at maximal concentration and elimination half-life were longer for 10 mg transdermal methimazole (5.2 (SD 1.1) hours and 13 (SD 3) hours, respectively) compared to 5 mg oral carbimazole (2.1 (SD 1.6) hours and 5.1 (SD 1.2) hours, respectively). At 148 hours, mean concentrations of methimazole in serum were higher in cats receiving 10 mg methimazole transdermally (506 (SD 165) ng/mL) than for 5 mg oral carbimazole (255 (SD 28) ng/mL) or 5 mg transdermally (204 (SD 76) ng/mL). The mean relative bioavailability of 10 mg transdermal methimazole compared to oral carbimazole was 48 (min 43, max 55)%. CONCLUSION: Transdermal methimazole at a dose of 10 mg administered to the pinnae of healthy cats once daily in a novel lipophilic formulation has half the relative bioavailablity compared to 5 mg oral carbimazole. CLINICAL RELEVANCE: Transdermal methimazole can be absorbed from the skin of healthy cats.

Optimization of ion-pair based hollow fiber liquid phase microextraction combined with HPLC-UV for the determination of methimazole in biological samples and animal feed.

Ion-pair based hollow fiber liquid phase microextraction (IP-HFLPME) coupled with high performance liquid chromatography-ultraviolet detection was applied for the preconcentration and determination of methimazole in biological samples and animal feed. Optimization of the conditions for the high extraction efficiency was studied simultaneously using the experimental design. For the first step, the Plackett-Burman design was applied to screen the significant factors on the extraction efficiency. Central composite design (CCD) was then used for the optimization of important factors and the response surface equations were obtained. The optimum experimental conditions were donor phase pH, 12.2; extraction temperature, 45°C; extraction time, 50 min; sodium perchlorate concentration, 1.5 M; cetyltrimethylammonium bromide concentration, 0.65 mM, and without salt addition in donor phase. The limit of detection and the dynamic linear range were in the range of 0.1-0.7 µg L(-1) and 0.5-1000 µg L(-1), respectively. Preconcentration factors were obtained in the range of 93-155 in different matrices. Finally, the performance of the proposed method was tested for the determination of trace amounts of methimazole in plasma, urine, bovine milk, and animal feed samples, and satisfactory results were obtained (RSDs < 7.1%).

The efficacy and safety of a novel lipophilic formulation of methimazole for the once daily transdermal treatment of cats with hyperthyroidism.

BACKGROUND: Previous studies on transdermal methimazole have used pluronic lecithin organogel as the vehicle. This might not be the most suitable vehicle for a lipophilic drug, such as methimazole. HYPOTHESIS/OBJECTIVES: Once daily transdermal administration of a novel lipophilic formulation of methimazole is as safe and effective as oral carbimazole in treating hyperthyroidism in cats. ANIMALS: Forty-five client-owned cats diagnosed with hyperthyroidism. METHODS: Prospective study. Cats with newly diagnosed, untreated hyperthyroidism were treated with carbimazole (5 mg p.o., q12h) or methimazole (10 mg) applied to the inner pinnae q24h. Cats were examined after 0, 1, 4, 8, and 12 weeks of treatment. Clinical signs, body weight, systolic blood pressure, hematologic, serum biochemical and urine parameters, total serum thyroxine concentrations (TT4), and serum methimazole concentrations were recorded. RESULTS: No significant differences between groups were detected at day 0. Both formulations were effective in treating hyperthyroidism. No significant differences were detected in thyroxine concentrations, body weight, blood pressure, heart rate, alkaline phosphatase, alanine aminotransferase, creatinine, urea, and urine specific gravity (USG) between groups. The serum methimazole concentrations correlated poorly with TT4-concentrations in both groups. CONCLUSIONS AND CLINICAL IMPORTANCE: In this 12-week trial, once daily application of a novel formulation of transdermal methimazole applied to the pinnae was as effective and safe as twice daily oral carbimazole in the treatment of cats with hyperthyroidism. This novel formulation and transdermal application could have practical advantages to some pet owners.

Electrochemical determination of methimazole based on the acetylene black/chitosan film electrode and its application to rat serum samples.

A novel method has been developed for the determination of methimazole, which was based on the enhanced electrochemical response of methimazole at the acetylene black/chitosan composite film modified glassy carbon electrode. The electrochemical behavior of methimazole was studied at this film electrode by cyclic voltammetry and differential pulse voltammetry. The experimental results showed that methimazole exhibited a remarkable oxidation peak at 0.63V at the film electrode. Compared with the bare glassy carbon electrode, the oxidation peak current increased greatly, and the peak potential shifted negatively, which indicated that the acetylene black/chitosan film electrode had good catalysis to the electrochemical oxidation of methimazole. The enhanced oxidation current of methimazole was indebted to the nano-porus structure of the composite film and the enlarged effective electrode area. The influences of some experimental conditions on the oxidation of methimazole were tested and the calibration plot was examined. The results indicated that the differential pulse response of methimazole was linear with its concentration in the range of 1.0×10(-7) to 2.0×10(-5)mol/L with a linear coefficient of 0.998, and in the range of 4.0×10(-5) to 3.0×10(-4)mol/L with a linear coefficient of 0.993. The detection limit was 2.0×10(-8)mol/L (S/N=3). The film electrode was used to detect the content of methimazole in rat serum samples by the standard addition method with satisfactory results.

A novel method for sensing of methimazole using gold nanoparticle-catalyzed chemiluminescent reaction.

Based on the inhibition effect of methimazole (MMI) on the reaction of luminol-H(2)O(2) catalyzed by gold nanoparticles, a novel chemiluminescence (CL) method was developed for the determination of MMI. Under the optimum conditions, the relative CL intensity was linearly related to MMI concentration in the range from 5.0 × 10(-8) to 5.0 × 10(-5) mol L(-1). The detection limit was 1.6 × 10(-8) mol L(-1) (S/N=3), and the RSD for 6.0 × 10(-6) mol L(-1) MMI was 4.83 (n=11). This method has high sensitivity, wide linear range, inexpensive instrumentation and has been applied to detect MMI in pharmaceutical tablets and pig serum samples. Furthermore, a possible reaction mechanism is discussed.

Serum concentrations of methimazole in cats after a single oral dose of controlled-release carbimazole or sugar-coated methimazole (thiamazole).

Methimazole (thiamazole) is an antithyroid drug commonly used to treat feline hyperthyroidism. It is routinely given twice daily. Carbimazole is a methimazole derivative that is rapidly metabolized to methimazole in vivo. A controlled-release tablet for once-daily carbimazole therapy has recently been developed in an attempt to improve compliance during medical management of feline hyperthyroidism. The results of a crossover study in six cats suggest that the pharmacokinetics of methimazole with a single dose of this controlled-release tablet may be similar to those with a single dose of a sugar-coated methimazole tablet when the two drugs are given at an equimolar dose. The mean half-lives were nearly identical (3.12 hours, sugar-coated methimazole tablets; 3.28 hours, controlled-release carbimazole tablets). The serum concentrations of methimazole at 24 hours were 21.7 ± 28.9 ng/mL in the cats treated with 5-mg sugar-coated methimazole tablets and 28.7 ± 37 ng/mL in the cats treated with 10-mg carbimazole tablets (which provide approximately 25% more methimazole after conversion to the active metabolite).

Pharmacokinetics of controlled-release carbimazole tablets support once daily dosing in cats.

Carbimazole, a prodrug of methimazole, is used in the treatment of hyperthyroidism in cats. The pharmacokinetics of methimazole was investigated in healthy cats following oral administration of 15 mg of carbimazole as a controlled-release tablet (Vidalta), Intervet). The controlled-release tablet did not produce a pronounced concentration peak and methimazole was present in the circulation for a sustained period, compared with a conventional tablet formulation. The time to reach peak concentrations after carbimazole administration was quite long (t(max) 6 h). The absolute bioavailability of carbimazole was around 88 +/- 11%. Repeated oral administration daily for 13 consecutive days did not lead to accumulation of methimazole in plasma. The extent of absorption of carbimazole was about 40% higher when administered to cats that had been fed compared to fasted cats. The relative oral bioavailability of methimazole following administration of the controlled-release tablets was similar to that of a conventional release formulation (83 +/- 21%). The pharmacokinetics of this controlled-release formulation of carbimazole supports its use as a once daily treatment (both as a starting dose and for maintenance therapy) for cats with hyperthyroidism.

Therapeutic drug monitoring of antithyroid drugs in pregnancy: the knowledge gaps.

Despite being a common condition in pregnancy, and despite propylthiouracil (PTU) being perceived as safer than methimazole, there are virtually no epidemiological controlled studies on malformation rate an neurobehavioral outcomes with the former. This knowledge gap must be filled to ensure fetal safety.

Thyroid function in breast-fed infants is not affected by methimazole-induced maternal hypothyroidism: results of a retrospective study.

For many years, breast-feeding was forbidden if methimazole (MMI) was being used. However, a few studies have demonstrated the relative safety of MMI. The purpose of this study was to evaluate thyroid function of breast-fed infants whose lactating mothers became hypothyroid while taking methimazole. Between 1990 and 2001, 134 thyrotoxic lactating mothers received MMI while breast-feeding. MMI therapy was initiated between 2-8 months postpartum, 10-30 mg for the first month and 5-10 mg from the second until the twelfth month. In 16 mothers, TSH was increased at the end of one month of MMI therapy (Group 1). Infants of 18 mothers whose serum TSH was normal at the end of the first month were included as controls (Group 2). Mothers and their infants were clinically evaluated and serum T4, T3 and TSH were measured before and at 1, 2, 4, 8 and 12 months after MMI therapy. Serum MMI was measured in 8 infants 2 h after breast-feeding. Mean +/- SD of FT4I and FT3I were not statistically different between the two groups of mothers before MMI therapy. In all 34 mothers thyroid indices decreased one month after MMI therapy; FT4I: Group 1 from 19.8 +/- 4.3 to 6.0 +/- 4.8 (p<0.001) and Group 2 from 20.3 +/- 4.7 to 11.4 +/- 4.1 (p<0.001); FT3I: Group 1 from 602 +/- 56 to 146 +/- 52 (p<0.001) and Group 2 from 562 +/- 42 to 186 +/- 39 (p<0.001). The difference in FT4I, FT3I and TSH (20 +/- 18 vs 2.1 +/- 1.1 mU/l, p<0.001) between the 2 groups was significant at the end of the first month of MMI therapy. There was no significant difference in thyroid function of infants of these two groups one month after MMI therapy and all tests remained within the normal range during 12 months of treatment of their lactating mothers. Serum MMI levels were less than 0.03 in 6 and 0.03 and 0.035 microg/ml in the other 2 infants. The results further indicate the safety of MMI therapy in breast-feeding thyrotoxic women.

Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats.

The antithyroid drug methimazole is widely used for the medical management of feline hyperthyroidism. Recently, custom veterinary pharmacies have offered methimazole in a transdermal gel containing pluronic and lecithin (PLO), with anecdotal evidence of efficacy. The purpose of this study was to determine the bioavailability, relative to i.v. and oral routes of administration, of transdermal methimazole in a PLO gel in cats. Six healthy adult cats were assigned to receive 5 mg of methimazole by the i.v., oral, or transdermal routes, in a randomized triple crossover protocol with 1 week washout between doses. Blood samples were taken for high performance liquid chromatography (HPLC) determination of serum methimazole, at 0, 5, 15, 30, 60 min, and 2, 4, 6, 12 and 24 h after dosing. Methimazole absorption following transdermal administration was poor and variable, with only two of six cats achieving detectable serum methimazole concentrations at any time point following transdermal administration. Area under the concentration-time curve (AUC), maximum concentration (Cmax), and absolute bioavailability were all significantly lower for the transdermal route (0.39 +/- 0.63 microg h/mL, 0.05 +/- 0.09 microg/mL, and 11.4 +/- 18.7%, respectively) than for either i.v. (7.96 +/- 4.38 microg h/mL, 3.34 +/- 2.00 microg/mL, 100%) or oral routes (2.94 +/- 1.24 microg h/mL, 0.51 +/- 0.15 microg/mL, 40.4 +/- 8.1%). The results of this study indicate generally low to undetectable bioavailability of methimazole in a lecithin/pluronic gel given as a single transdermal dose to healthy cats, although one individual cat did achieve nearly 100% transdermal bioavailability relative to the oral route.

Methimazole-mediated enhancement of albendazole oral bioavailability and anthelmintic effects against parenteral stages of Trichinella spiralis in mice: the influence of the dose-regime.

The influence of methimazole (MTZ) inhibitor of the microsomal oxidases on the systemic availability of the albendazole sulpho-metabolites (ABZS-MT) albendazole-sulphoxide (ABZSO) and albendazole-sulphone (ABZSO2) and on its anthelmintic effects was investigated in a mouse model for helminthic infections. Plasma concentrations of the ABZS-MT were measured by high performance liquid chromatography (HPLC) following treatment of Swiss CD-1 mice with albendazole (ABZ) alone or ABZ plus MTZ, at both single and repeated doses. The anthelmintic effects were assessed in age-matched mice similarly treated following infection with Trichinella spiralis. MTZ significantly (p < 0.01) increased the ABZS-MT plasma concentrations although the pharmacokinetic profile varied greatly according to the dose of ABZ administered. When ABZ was given at a single dose of 50 mg/kg followed by MTZ at 3 mg/kg, a cumulative effect was observed in the ABZS-MT plasma levels with pharmacokinetic parameters (Tmax = 24 h, Cmax= 30.88 microg/ml and AUC = 1120.80 microg h/ml) significantly ( p < 0.01) higher than those following administration of ABZ alone (Tmax = 3 h, Cmax = 11.00 microg/ml and AUC = 268.03 microg h/ml). This cumulative effect was absent following administration of ABZ at 100 mg/kg where, after reaching a maximum (Cmax = 27.23 microg/ml) at 3 h post-administration (Tmax), the ABZS-MTplasma levels felt down quickly to values under those obtained after administration of ABZ at the same dose, but alone (AUC = 362.15 microg h/ml vs. 340.15 microg h/ml, respectively). When ABZ was given at 50 mg/kg together with MTZ three times every 24 h, a rapid decrease was observed in the ABZS-MT plasma levels following administration of both the second and third doses, respectively. The pharmacokinetic profile of ABZS-MT following administration of each of the three doses of ABZ at 100 mg/kg plus MTZ was the same as that obtained after the single treatment. The rapid decrease of the ABZS-MT plasma levels observed after the sustained treatment or after the single treatment at 100 mg/kg could be due to a microsomal oxidase inductive effect (probably the cytochrome P-450) caused by ABZSO. The co-administration of MTZ significantly (p < 0.01) increased the anthelmintic effects of ABZ against both migrating and encysted larvae of T. spiralis. Repeated treatment did not improve the anthelmintic effects of the single treatment as the efficacies against both stages of the parasite were always lower or identical to those of the single treatment at the corresponding doses.

Comparison of the disposition of carbimazole and methimazole in clinically normal cats.

The oral disposition of the antithyroid drugs methimazole and carbimazole were compared in nine clinically normal cats. After the administration of 5 mg of methimazole, serum concentrations of methimazole increased in all the cats, with mean drug concentrations reaching peak values (1.37 micrograms ml-1) at 30 minutes. After administration of 5 mg carbimazole, serum concentrations of carbimazole remained low, but serum methimazole became readily measurable, with mean drug concentrations reaching peak values (0.79 microgram ml-1) at 120 minutes. When serum concentrations of methimazole attained after administration of the two antithyroid drugs were compared, the mean maximum serum methimazole concentration achieved after administration of methimazole was approximately twofold higher than peak concentrations measured after administration of carbimazole. In addition, the mean area under the serum concentration curve (AUC) after administration of methimazole was approximately twofold higher than the mean AUC determined after administration of carbimazole. When the differences in molecular weight between the two drugs was taken into consideration, however, these methimazole:carbimazole ratios of 2:1 were nearly equivalent to the molar ratio of the 5 mg doses of the drugs given (1.63). Results of this study indicate that carbimazole is nearly totally converted to methimazole after oral administration to cats, similarly to the findings in man. The finding of less available serum methimazole after administration of a 5 mg tablet of carbimazole than after methimazole is also consistent with published antithyroid drug dosages needed to control hyperthyroidism in cats.

Methimazole-mediated modulation of netobimin biotransformation in sheep: a pharmacokinetic assessment.

The effects of modulation of liver microsomal sulphoxidation on the disposition kinetics of netobimin (NTB) metabolites were investigated in sheep. A zwitterion suspension of NTB was given orally at 7.5 mg/kg to sheep either alone (control treatment) or co-administered with methimazole (MTZ) orally (NTB + MTZ oral treatment) or intra-muscularly (NTB + MTZ i.m.) at 3 mg/kg. Blood samples were taken serially over a 72 h period and plasma was analysed by HPLC for NTB and its major metabolites, i.e. albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2). Only trace amounts of NTB parent drug and ABZ were detected in the earliest samples after either treatment. There were significant modifications to the disposition kinetics of ABZSO in the presence of MTZ. ABZSO elimination half-life increased from 7.27 h (control treatment) to 14.57 h (NTB + MTZ oral) and to 11.39 h (NTB + MTZ i.m.). ABZSO AUCs were significantly higher (P less than 0.05) for the NTB + MTZ oral treatment (+55%) and for the NTB + MTZ i.m. treatment (+61%), compared with the NTB alone treatment. The mean residence times for ABZSO were 12.66 +/- 0.68 h (control treatment), 18.85 +/- 2.35 h (NTB + MTZ oral) and 17.02 +/- 0.90 h (NTB + MTZ i.m.). There were no major changes in the overall pharmacokinetics of ABZSO2 for the concomitant MTZ treatments. However, delayed appearance of this metabolite in the plasma resulted in longer ABZSO2 lag times and a delayed Tmax for treatments with MTZ.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic parameters of thiamazole in hyperthyroid patients responding rapidly and slowly to the treatment.

Pharmacokinetic parameters of thiamazole were compared in two groups of patients with hyperthyroidism due to Graves-Basedow disease, differing in the period required to achieve clinical euthyrosis (less than 28 days, group R, n = 23, and not less than 35 days, group D, n = 18) after treatment with the "full" dose of the drug. The drug absorption from the GI tract in both groups was similar, but the serum concentrations of the drug (Cmax and AUC) were higher, and distribution volume and total clearance lower in the R than in D group. No evidence was found for the importance of initial plasma levels of thyroxine or triiodothyronine on pharmacokinetic parameters of thiamazole.