Bioavailability of propylthiouracil from two formulation tablets.

Bioavailability studies were performed for 50 mg propylthiouracil tablets (Jelfa, Poland) versus 50 mg propycil tablets (Solvay, Germany). An open-label, two-phase, crossover study was conducted with 15 healthy subjects. All subjects were randomly assigned a drug assignment number from I to XV, which was used throughout the experimental period. Dosing periods for both formulation tablets: Propylthiouracil, Jelfa vs. Propycil, Solvay were separated by at least 7 days washout period. Following single dose drug administration, venous blood samples were obtained at the required times for 12 h and the drug serum levels were determined by HPLC and used for PK analysis. PK parameters were calculated by the computer program TopFit 2.0. HPLC chromatograms show retention times for propylthiouracil and methylthiouracil (internal standard) of 5.97 and 2.75 min, respectively at 20 °C, providing adequate separation from each other and from endogenous serum components. Pharmacokinetic parameters for both tablets were not significantly different. Serum concentration-time profiles are superimposed for the above tablets according to an open one-compartment body model. EBA for Propythiouracil Jelfa tablets vs. Propycil tablets was 96.8%, and not significantly different. Some authors applied a two-compartment body model for the calculation of propylthiouracil pharmacokinetic parameters, which approach is not rational according to our data.

Propylthiouracil-coated biodegradable polymer inhibited neointimal formation and enhanced re-endothelialization after vascular injury.

BACKGROUND: The drug-eluting stent is a standard approach for the treatment of coronary artery disease. Propylthiouracil (PTU), an antithyroid drug, has been proven to suppress neointimal formation after balloon injury. MATERIALS AND METHODS: This study used a biodegradable polymer coating with PTU to test its effects on platelet function, re-endothelialization, and neointimal formation after vascular injury. Electrospinning was used to fabricate hybrid stents and generate PTU-loaded nanofibers. RESULTS: PTU-eluting stents maintained a stable release of PTU for 3 weeks. The PTU-coated stent markedly decreased the neointimal formation induced by vascular injury in the descending aorta of rabbits. Moreover, the PTU coating reduced platelet adhesion on the surface of the biodegradable membrane, which was reflected by the decreased expression of adhesion molecule in PTU-treated endothelial cells. The PTU coating enhanced re-endothelialization in injured aortas. In vitro, PTU exerted less suppressive effect on the proliferation and migration of endothelial cells than on those of vascular smooth muscle cells. Furthermore, treatment of endothelial cells with PTU induced phosphorylation (Ser1177) of endothelial nitric oxide synthase as well as its association with heat shock protein 90, supporting the protective role of PTU in endothelial function. The level of thyroid-stimulating hormone remained unchanged during the experimental period. CONCLUSION: This study indicates that PTU can be released locally and steadily in injured aortas, with some local effects but without systemic effects. Furthermore, PTU-coated stents may have beneficial effects on neointimal formation, endothelial cell, and platelet functions.

Dose-dependent effects of perinatal hypothyroidism on postnatal testicular development in rat offspring.

The role of thyroid hormones in gonad development remains incompletely understood. We examined the dose-related effects of perinatal hypothyroidism induced by a reversible goitrogen, 6-propyl-2-thiouracil (PTU), on reproductive development in male rat offspring. Timed-pregnant Sprague-Dawley rats were orally administered PTU (0, 0.5, 1.0, or 2.0 mg/kg/day) by gavage from gestational day 15 through postnatal day 20. We observed a significant dose-dependent decrease in body weight in offspring with PTU exposure up to 13 weeks of age, but body weight became comparable among groups by 26 weeks of age. Testicular weight tended to be lower up to 7 weeks but was higher after 13 weeks of age. Epididymis weight was not different among the groups at any age. Plasma concentrations of thyroxine and triiodothyronine in the PTU groups were significantly lower at 3 weeks of age but recovered to normal levels by 26 weeks of age. No dose-related trend in plasma testosterone concentrations was found. Seminiferous tubules were larger at 13 and 26 weeks of age with PTU exposure. The number of Sertoli cells was significantly higher from 3 through 26 weeks of age. The number of Leydig cells was significantly lower up to 7 weeks of age but was comparable among groups from 13 weeks of age onwards. Thus, transient gestational and lactational thyroid hormone suppression induced small testes in early life but led to paradoxical dose-dependent testicular enlargement in adults as indicated partly by larger seminiferous tubules with numerous Sertoli cells in male rat offspring.

Propylthiouracil quantification in human plasma by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry: application in a bioequivalence study.

UNLABELLED: A rapid, sensitive and specific method for quantifying propylthiouracil in human plasma using methylthiouracil as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by liquid-liquid extraction using an organic solvent (ethyl acetate). The extracts were analyzed by high performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS) in negative mode (ES-). Chromatography was performed using a Phenomenex Gemini C18 5µm analytical column (4.6mm×150mm i.d.) and a mobile phase consisting of methanol/water/acetonitrile (40/40/20, v/v/v)+0.1% of formic acid. For propylthiouracil and I.S., the optimized parameters of the declustering potential, collision energy and collision exit potential were -60 (V), -26 (eV) and -5 (V), respectively. The method had a chromatographic run time of 2.5min and a linear calibration curve over the range 20-5000ng/mL. The limit of quantification was 20ng/mL. The stability tests indicated no significant degradation. This HPLC-MS/MS procedure was used to assess the bioequivalence of two propylthiouracil 100mg tablet formulations in healthy volunteers of both sexes in fasted and fed state. The geometric mean and 90% confidence interval CI of Test/Reference percent ratios were, without and with food, respectively: 109.28% (103.63-115.25%) and 115.60% (109.03-122.58%) for Cmax, 103.31% (100.74-105.96%) and 103.40% (101.03-105.84) for AUClast. CONCLUSION: This method offers advantages over those previously reported, in terms of both a simple liquid-liquid extraction without clean-up procedures, as well as a faster run time (2.5min). The LOQ of 20ng/mL is well suited for pharmacokinetic studies. The assay performance results indicate that the method is precise and accurate enough for the routine determination of the propylthiouracil in human plasma. The test formulation with and without food was bioequivalent to reference formulation. Food administration increased the Tmax and decreased the bioavailability (Cmax and AUC).

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.

Pathogenesis of propylthiouracil-related hepatotoxicity in children: present concepts.

Propylthiouracil (PTU), carbimazole (CMZ) and methimazole (MMI) are the most common drugs used today in cases of adolescent thyrotoxicosis. Skepticism has been growing regarding the use of PTU in childhood and its association with severe liver failure. The aim of this review is to present all the recent data regarding pathogenesis of PTU hepatotoxicity in children and adolescents. Specifically, reactive drug metabolites and increased oxidative stress can directly activate inflammatory and immunological pathways. Drugs are not only immunogenic because of their chemical reactivity but also because they may bind through electrostatic forces to available T-cell receptors. Redox modulation is also a key regulatory strategy in the adaptive immune system. Subtle changes in the extracellular redox status may cause profound functional changes in redox-sensitive proteins. Genetic factors that affect drug biotransformation could also be implicated in this mechanistic model of PTU-related hepatotoxicity. Further studies are needed to fully understand the pathophysiology of PTU-induced liver damage.

Management of hyperthyroidism during pregnancy and lactation.

INTRODUCTION: Poorly treated or untreated maternal overt hyperthyroidism may affect pregnancy outcome. Fetal and neonatal hypo- or hyper-thyroidism and neonatal central hypothyroidism may complicate health issues during intrauterine and neonatal periods. AIM: To review articles related to appropriate management of hyperthyroidism during pregnancy and lactation. METHODS: A literature review was performed using MEDLINE with the terms 'hyperthyroidism and pregnancy', 'antithyroid drugs and pregnancy', 'radioiodine and pregnancy', 'hyperthyroidism and lactation', and 'antithyroid drugs and lactation', both separately and in conjunction with the terms 'fetus' and 'maternal.' RESULTS: Antithyroid drugs are the main therapy for maternal hyperthyroidism. Both methimazole (MMI) and propylthiouracil (PTU) may be used during pregnancy; however, PTU is preferred in the first trimester and should be replaced by MMI after this trimester. Choanal and esophageal atresia of fetus in MMI-treated and maternal hepatotoxicity in PTU-treated pregnancies are of utmost concern. Maintaining free thyroxine concentration in the upper one-third of each trimester-specific reference interval denotes success of therapy. MMI is the mainstay of the treatment of post partum hyperthyroidism, in particular during lactation. CONCLUSION: Management of hyperthyroidism during pregnancy and lactation requires special considerations and should be carefully implemented to avoid any adverse effects on the mother, fetus, and neonate.

Interaction of antithyroid drugs with bovine serum albumin: electrophoretic and fluorimetric study.

The pre-equilibrium capillary zone electrophoretic (pre-eq CZE) method to determine association constants of active anionic forms of antithyroid drugs: 6-n-propyl-2-thiouracil (PTU), 6-methyl-2-thiouracil (MTU), 2-thiouracil (TU) with bovine serum albumin (BSA) under physiological pH 7.4 has been developed for the first time. Using the decrease of the selective electrochromatographic peak area of a drug anionic form due to binding with BSA the association constants K of the binary BSA complexes were calculated. It has been found that the binding constants (log K) of BSA with TU, MTU, and PTU are equal to 2.99, 1.85, and 2.11, respectively. The interaction of PTU, MTU, TU, 2-mercapto-1-methylimidazole (MMI), and ethyl-3-methyl-2-thionoimidazoline-1-carboxylate (Carb), which is considered to be a prodrug for MMI, with BSA has been investigated under physiological conditions by means of fluorescence spectroscopy. Fluorescence emission spectra of BSA in the presence of thioamides recorded at 295 nm excitation wavelength clearly show that the studied drugs act as quenchers, except MMI, which acts as quencher when being excited at 280 nm. The 295 nm light excites tryptophan residues, while the 280 nm light excites both tryptophan and tyrosine residues. The binding constants (log K) of BSA with PTU, MTU, TU, MMI, and Carb have been found to be 4.51, 4.30, 4.30, 2.64, and 4.32, respectively.

Epididymis expresses the highest 5'-deiodinase activity in the male reproductive system: kinetic characterization, distribution, and hormonal regulation.

We characterized the enzymes that catalyze the deiodination of T(4) to T(3) in the male reproductive tract. Testis, epididymis (EPI), seminal vesicles, prostate, bulbourethral glands, spermatozoa, and semen were taken from sexually mature rats (300 g). Iodothyronine 5'-deiodinase (5'-D) activity was quantified by the radiolabeled-iodide-release method. 5'-D activity was 10-fold higher in EPI and semen than in the rest of the tissues. In EPI, semen, and prostate, the enzymatic activity was completely inhibited by 1 mm 6-n-propyl-2-thiouracil, whereas in the other tissues the inhibition was partial (50%). The high susceptibility to 6-n-propyl-2-thiouracil inhibition, a ping-pong kinetic pattern, and low cofactor (Michaelis Menten constant for dithiothreitol=0.7 mm) and high substrate (Michaelis Menten constant for reverse T(3)=0.4 microm) requirements indicate that EPI 5'-D corresponds to type 1 deiodinase (D1). Real-time RT-PCR amplification of D1 mRNA in this tissue confirms this conclusion. The highest EPI D1 expression occurred at the onset of puberty and sexual maturity, and in the adult, this activity was more abundant in corpus and caput than in the caudal region. EPI D1 expression was elevated under conditions of hyperthyroidism and with addition of 17beta-estradiol. Our data also showed a direct association between D1 and a functional epididymis marker, the neutral alpha-glucosidase enzyme, suggesting that local generation of T(3) could be associated with the development and function of EPI and/or spermatozoa maturation. Further studies are necessary to analyze the possible physiological relevance of 5'-D in the male reproductive system.

[Current problems in the treatment of Graves' disease in pregnancy and in lactation].

In Graves' patients complicated by pregnancy, both maternal and fetal problems related to the disease can be reduced or avoided by controlling hyperthyroidism. However, optimal treatment for mothers may exert detrimental effects on fetuses. Methimazole may cause "methimazole embryopathy". Antithyroid drug doses that maintain mothers in euthyroid status are sometimes excessive fetuses. Furthermore, successful treatment with surgery or radioiodine occasionally may result in fetal hyperthyroidism due to TSH receptor antibody(TRAb). There are approaches to manage these problems. Propylthiouracil is chosen in treating Graves' disease in early pregnancy. In later pregnancy, maternal free thyroxine is maintained near or somewhat above normal. Ablative therapy is not recommended in women whose TRAb levels are extremely high from the standpoint of fetal thyroid state.

Pharmacokinetics and pharmacotherapy of thionamides in pregnancy.

Hyperthyroidism occurs in approximately 1 in every 1000 to 2000 pregnancies. Although the signs and symptoms of the disease are similar in the pregnant and nonpregnant patient, the complications of hyperthyroidism can have even more profound consequences for the mother and fetus during gestation. These include maternal heart failure, preeclampsia, miscarriage, and preterm labor; as well as fetal loss and low birth weight. Furthermore, thyroid function and laboratory testing for hyperthyroidism are altered in pregnancy. The gestational increase in thyroid size, increased thyroid-binding globulin levels, increased serum total T4 and total T3 levels, and decreased thyroid stimulating hormone levels often confuses the evaluation of the thyroid status in pregnancy. Worldwide, the thionamides-propylthiouracil, methimazole, and carbimazole-have been used in pregnancy for the treatment of hyperthyroidism. However, propylthiouracil has been the drug of choice in the United States because it is believed to have less potential to induce fetal/neonatal hypothyrodism, to cross the placenta and into breast milk to a lesser degree, and to be less teratogenic than methimazole or carbimazole. None of the above have been substantiated in more recent studies. The pharmacokinetics of the thionamides in the pregnant and nonpregnant states, as well as the pharmacotherapeutic recommendation for hyperthyroidism will be reviewed.

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.

Old drugs - old people - new insights.

Dr. Dan Sitar was the recipient of the 2004 CSCP Senior Investigator Award at the First Canadian Therapeutics Congress held in June 2004. He presented a lecture highlighting some of the studies he participated in that have contributed to an increased understanding of the role of aging on drug disposition and effect.

Enhanced rat Hershberger assay appears reliable for detection of not only (anti-)androgenic chemicals but also thyroid hormone modulators.

Development of an internationally recognized standard for the Hershberger assay as a screening tool to detect potential (anti-)androgenic chemicals is in progress. In the present preliminary study, we evaluated the reliability of the enhanced Hershberger assay to detect thyroid hormone modulating activity, while concentrating attention on possible confounding influence on evaluation of (anti-)androgenic activity. Castrated or testosterone propionate (TP; 0.2 or 0.25 mg/kg/day)-injected castrated male Crj:CD(SD) IGS rats (seven weeks of age) were dosed for 10 days by oral gavage with vehicle (corn oil) or the following chemicals: propylthiouracil (PTU; 2.5 mg/kg/day), a potent inhibitor of thyroid hormone synthesis, phenobarbital (PB; 125 mg/kg/day) and 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE; 100 mg/kg/day), two hepatic enzyme inducers that enhance the clearance of thyroid hormones. PTU markedly increased thyroid weights, and decreased serum T3 and T4, and increased serum TSH, also causing marked microscopic alteration of the thyroid gland. In comparison, PB and p,p'-DDE only significantly affect serum T4 and revealed some histopathological findings. The alterations appeared to be more robust in the presence of TP. Furthermore, data for p,p'-DDE demonstrated its anti-androgenic effects, whereas PTU and PB had little or no effects on the weights of androgen-related accessory glands/tissues: the ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, glans penis, Cowper's glands, and levator ani plus bulbocavernosus (LABC) muscles. Weight of the LABC muscles was decreased by PB treatment in TP-treated castrated rats. These findings in the present study suggests that the enhanced Hershberger assay, with evaluation of thyroid histopathology and weights, and hormone levels, appears to be reliable for screening for not only (anti-)androgenic chemicals but also thyroid hormone modulators. In order to evaluate whether the sensitivity and specificity of such a thyroid assay is great enough for routine screening purposes, future experiments including dose-response studies using lower dose levels have to be performed.

Detection of endocrine-modulating effects of the antithyroid acting drug 6-propyl-2-thiouracil in rats, based on the "Enhanced OECD Test Guideline 407".

The antithyroid acting drug propylthiouracil (PTU) was administered to male and female Wistar rats at 0, 0.1, 1, or 10mg/kg body weight for 4 weeks according to the draft protocol of the "Enhanced OECD Test Guideline 407" (enhanced TG 407) in order to investigate its suitability to detect endocrine-mediated effects. The study was conducted with two identical subsets of five animals per sex and dose each to provide data on sensitivity. The modified protocol includes the investigation of additional organ weights, pathology, and histopathology, of thyroid hormones, of spermatozoa, and of estrus cycle. At time of sacrifice, all females were in the diestrus stage as prescribed. Adverse effects were observed in the thyroid gland (hypertrophy/ hyperplasia) and the pituitary gland (hyperplasia of basophilic cells, hypoplasia of acidophilic cells) together with dose-related decreased serum triiodothyronine (T3) and thyroxine (T4) levels and increased thyroid stimulating hormone (TSH) levels. Other effects of PTU included decrease of organ weights, anaemia, impaired blood coagulation, and reduced activity of enzymes. Hence, some of the additional examined endpoints of the enhanced TG 407, e.g., examination of pituitary gland and thyroid hormones, were suitable to detect endocrine-modulating effects of propylthiouracil. Treatment of five animals provides sufficient sensitivity to detect the described adverse effects of propylthiouracil. The enhanced TG is currently under investigation in several laboratories, evaluation of all the results will allow determining its practicability as well as the most suitable additional endpoints.

Genetic taste responses to 6-n-propylthiouracil among adults: a screening tool for epidemiological studies.

Genetically mediated taste responsiveness to 6-n-propylthiouracil (PROP) has been linked to reduced acceptance of some bitter foods. In this community-based study male (n = 364) and female (n = 378) adults enrolled in a self-help dietary intervention trial were screened for PROP taster status. Respondents, aged 18--70 years, were mailed filter papers impregnated with PROP or with aspartame solutions. They received instructions to rate taste intensity and hedonic preference using nine point category scales. Women rated PROP as more bitter than did men. Both sweetness and bitterness ratings were lower for older adults. Taste responsiveness to PROP was unrelated to body mass index in women or men. Higher bitterness ratings for PROP were weakly associated with higher sweetness ratings for aspartame, but were unrelated to sweet taste preferences. Successful administration of PROP filter papers by mail suggests new avenues for the screening of taste phenotypes in epidemiological studies.

Tratamiento del hipertiroidismo por enfermedad de Basedow-Graves: visión retrospectiva al cabo de 30 años / Treatment of Basedow-Graves hyperthyroidism: retrospective analysis after 30 years

Background: It is still debated which is the best treatment for Basedow-Graves' hyperthyroidism (BGH). We reviewed 195 patients treated and followed-up during the past 30 years: 88 treated with propylthiouracil (PTU), 70 with 131I and 37 thyroidectomized Aim: to analyze the efficacy of each therapy in terms of achieving euthyroidism and the search of possible indexes for success. Surgery attained euthyroidism in 70.2 percent but has disadvantages; 131I accounted for the highest hypothyroid rate (72.1percent) irrespective of the dose administered; PTU alone was successful in only 26.4 percent but combined with T4, success rose to 62.5 percent (p < 0.025). Suppression test and/or TRAb measurements after 6 mo PTU therapy were used to decide if therapy continued or was changed to other form of treatment. Using this criteria, 87.5 percent of pts with positive results achieved longstanding euthyroidism. Pretreatment predictive indexes were goiter size, T4 levels and 24 h/RAI uptake. Conclusions: As 131I induces hypothyroidism in over 2/3 of pts and surgery besides its cost is not devoid of serious complications, we advocate for the use of PTU as first line therapy; combined treatment (PTU + T4) seems promising. If after 6 mo on PTU, TRAb or Suppression test do not improve, we recommend 131I or surgery

Methimazole and propylthiouracil equally cross the perfused human term placental lobule.

Propylthiouracil (PTU) is widely believed to cross the placenta less freely than methimazole (MMI) and is therefore regarded as the preferred drug for treatment of hyperthyroidism in pregnancy. Clinical studies comparing the two drugs show, however, no differences in maternal or fetal thyroid function. We investigated transfer from the maternal to the fetal circuit in the isolated perfused term human placental lobule of low and high doses of PTU (4 micrograms/mL and 40 micrograms/mL) and MMI (1.5 micrograms/mL and 15 micrograms/mL) in protein-free perfusate and low doses of both drugs with addition of 40 g/L of bovine albumin. Both drugs readily crossed the placenta, reaching equilibrium in all experiments in about 2 h. Drug concentrations in the two circuits fitted a two compartmental model. Transfer kinetics for the two drugs were similar, nonsaturable, and unaffected by addition of albumin. Clearances (mL.min-1.g-1, means +/- SD) of PTU from maternal to fetal circuits were: 0.229 +/- 0.110, 0.216 +/- 0.065, and 0.170 +/- 0.032; and for transfer of MMI: 0.165 +/- 0.025, 0.232 +/- 0.153, and 0.174 +/- 0.009 (for low doses without, low doses with, and high doses without albumin, respectively). Clearances of PTU from fetal to maternal circuits were: 0.147 +/- 0.072, 0.109 +/- 0.014, and 0.116 +/- 0.028; and for transfer of MMI: 0.095 +/- 0.029, 0.122 +/- 0.088, and 0.12 +/- 0.005 (in the same experiments). There was no significant difference between drugs or drug doses and no effect of addition of albumin. We conclude that PTU and MMI have similar placental transfer kinetics.

Acute effects of propylthiouracil on hemodynamics and oxygen content in patients with alcoholic cirrhosis.

BACKGROUND/AIMS: The antithyroid drug propylthiouracil has been suggested for the treatment of alcoholic liver disease. Its beneficial effects could be due to either a decrease in hepatic oxygen consumption or an increase in hepatic blood flow. The aim of this study was to test these two hypotheses in patients with proven alcoholic cirrhosis. METHODS: The pharmacokinetic parameters after intravenous administration of 300 mg of propylthiouracyl were first determined in four patients. Then, the effects on systemic and splanchnic hemodynamics, and oxygen content were measured 45 and 90 min after the intravenous administration of 300 mg (n=6) or 600 mg (n=6) of propylthiouracil. RESULTS: Systemic hemodynamics (heart rate, arterial pressure, cardiac output and systemic vascular resistance) and splanchnic hemodynamics (hepatic venous pressure gradient, hepatic and azygos blood flows) were not modified 45 and 90 min after the administration of 300 mg or 600 mg of propylthiouracil. Moreover, neither oxygen content in the radial artery, pulmonary artery or hepatic vein, nor systemic oxygen uptake was modified after propylthiouracyl administration. The absence of effect of propylthiouracyl administration was also confirmed in patients with cirrhosis with proven acute alcoholic hepatitis (n=7). CONCLUSIONS: In patients with alcoholic cirrhosis, acute administration of propylthiouracyl has no effect on systemic and splanchnic hemodynamics or on oxygen contents. The presence of acute alcoholic hepatitis does not modify these results.

In-vivo evaluation in man of a hydrophilic matrix containing propylthiouracil.

To reduce the number of administrations of propylthiouracil required to treat hyperthyroidism, the bioavailability and sustained-release characteristics of 300 mg propylthiouracil formulated in hydrophilic matrix tablets were evaluated after single oral administration in healthy male volunteers. A conventional tablet was chosen as the reference formulation. For tablets formulated from three different types of hydroxypropylmethylcellulose, K15M, K4M and K100LV, propylthiouracil dissolution in-vitro was 40%, 51% and 100%, respectively, in 8 h. The three matrix formulations showed sustained plasma concentration-time profiles. The relative bioavailability was 50, 51 and 87%, respectively, for K4M, K15M and K100LV hydroxypropylmethylcellulose matrix tablets. When reverse triiodothyronine concentrations were plotted against the corresponding propylthiouracil concentrations, an antihysteresis loop was observed with the conventional tablets and the K100LV matrix tablet. A linear concentration-response curve was obtained for both the K4M and K15M formulations. The results showed that the K100LV matrix tablet gave a sustained plasma concentration-time profile and a bioavailability and extrathyroidal effect similar to that of a conventional tablet.