Metabolism of thioamide antithyroid drugs.

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Metabolism of Thioamide Antithyroid Drugs Daniel S. Sitar

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Clinical Pharmacology Section Faculty of Medicine University of Manitoba 770 Bannatyne Avenue Winnipeg, Manitoba, R3E 0W3, Canada Published online: 08 Jun 2015.

To cite this article: Daniel S. Sitar (1990) Metabolism of Thioamide Antithyroid Drugs, Drug Metabolism Reviews, 22:5, 477-502 To link to this article: http://dx.doi.org/10.3109/03602539008991448

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DRUG METABOLISM REVIEWS. 22(5). 477-502 (1990)


METABOLISM OF THlOAMlDE ANTITHYROID DRUGS* DANIEL S . SITAR Clinical Pharmacology Sectiori Faculty of Medicine University of Manitoba 770 Bannatyne Avenue Winnipeg. Manitoba R3E 0 W3 Canada

I . INTRODUCTION ..................................... 11. ANALYTICAL METHODS ............................. 111. ABSORPTION ........................................ IV . DISTRIBUTION ...................................... A . Pharmacokinetic Distribution .......................... B. General Tissue Distribution ........................... C. Thyroid Gland ...................................... D . Protein Binding ..................................... E . Formed Elements of Blood ........................... F. Placental Transfer ................................... V. EXCRETION ......................................... A . Urine ............................................. B. Breast Milk ........................................ C. Bile and Feces ...................................... VI . METABOLISM ....................................... A . Propylthiouracil ..................................... B. Methimazole ....................................... C. Drug Metabolism in Thyroid Dysfunction ............... VII . CONCLUSIONS ...................................... References ...........................................

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'This paper was refereed by Elliot S . Vesell. M.D., Chairman. Department of Pharmacology. The Milton S . Hershey Medical Center. Hershey. PA 17033. 477 Copyright 0 199 1 by Marcel Dekker. Inc .

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I. INTRODUCTION The advent of the antithyroid drugs in the 1940s [ l ] exerted a profound influence not only on the management of hyperthyroidism but also on the discipline of clinical pharmacology. Yet some fundamental aspects of the use of these drugs, as well as their pharmacokinetics, remain to be elucidated. Although thiouracil was the first widely used synthetic antithyroid drug, it was withdrawn from the market because of the frequency of side effects. Subsequently, propylthiouracil [2] and methimazole [3] were demonstrated to be useful synthetic antithyroid drugs with a better side effects profile in man than thiouracil. Shortly thereafter, Lawson and Barry [4] reported that the carbethoxy derivative of methimazole, carbimazole, was clinically effective in the treatment of hyperthyroidism. It was then demonstrated that carbimazole is quantitatively transformed to methimazole in vivo and that carbimazole after a therapeutic dose is not detectable in the circulation [5]. Thus, the disposition of carbimazole can be regarded as essentially the same as that of methimazole. The chemical structures of these three drugs are presented in Fig. 1. Although it was initially believed that the only difference between methimazole and propylthiouracil was a longer duration of action of methimazole with respect to inhibition of organification of iodine by the thyroid gland, it has been demonstrated that propylthiouracil,but not methimazole, also inhibits peripheral deiodination of thyroxine to triiodothyronine [HI.Our understanding of the disposition of these newer antithyroid drugs began only in 1969 [9] and has progressed substantially since then. However, our knowledge of the relationship of metabolism to side effect profile is still in its infancy. This review is directed at our present understanding of the disposition of propylthiouracil and methimazole, the only nonradioactiveantithyroid drugs used to any significant extent today. Those interested in the disposition of older antithyroid drugs, including thiouracil, are referred to Spector and Shideman [lo] and a review by Liberti and Stanbury [ll].

II. ANALYTICAL METHODS The first approach to detection of propylthiouracil and methimazole in biological fluids involved use of radiolabeled drugs [9,12-la]. This approach has remained popular even with more recent studies [17-201, especially for the quantitation of drug metabolites. Relatively specific chemical analytical methods for propylthiouracil and methimazole have been developed only since 1970. A colorimetric method

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THIOAMIDE METABOLISM

I


OH

FIG.1. Structures of the principal synthetic antithyroid drugs used for the treatment of hyperthyroidism: (1) propylthiouracil; (2) methimazole; (3) carbimazole.

developed by Ratliff et al. [21] has been used for the determination of propylthiouracil and methimazole with varying success. Gas-liquid chromatography was first described for the determinationof propylthiouracilby Schuppan et al. [22]. The first reported high pressure liquid chromatographic assay for propylthiouracil capable of detecting plasma concentrations after a therapeutic dose was described by Sitar and Hunninghake [23]. High pressure liquid chromatographic analysis of propylthiouracil and methimazole has been the most popular method for drug quantitation,and variations of this approach have been reported by several groups [24-281. Other analytical approaches, including radioimmunoassay [29,30] and gas chromatography-mass spectrometry, have also been reported [31].

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111. ABSORPTION

In man, Kampmann and Skovsted [32,33] estimated bioavailability of propylthiouracil to be 77 f 13% in euthyroid subjects and 76 f 14% in hyperthyroid subjects who received both i.v. and p.0. drug doses. The rate of absorption is rapid with peak plasma concentrations almost always within an hour after ingestion and similar for euthyroid and hyperthyroid adults and children [22, 23, 29, 34-37]. Although absorption of propylthiouracil is not different from euthyroid subjects in patients where it can be determined, it is erratic in the hypothyroid state [38]. Melander et al. [39] were not able to show any systemic effect of food on propylthiouracil absorption after a standard breakfast, and this observation has been confirmed [29]. Kampmann et al. [40] found that the absorption rate constant was reduced in elderly subjects, but not the extent of drug absorption. Available data from studies in rats indicate that absorption of propylthiouracil is rapid and at least as extensive as in man [13]. For methimazole, maximum plasma concentration occurs at somewhat more variable times than for propylthiouracil. Okamura et al. [41] determined a time to peak of about 2 h in their subjects, while Jansson et al. [5] reported peak methimazole concentrations at about 1 h after the drug dose. No difference in time to peak concentration for methimazole has been demonstrated after p.0. doses of carbimazole and methimazole [5,42,43]. Absorption of methimazole in animal studies gives peak concentrations in rats at about 1 h, and the bioavailability based on urinary excretion of radioactivity appears to be high and similar to data from human subjects assessed in the same way [9,14]. Early preliminary data indicated that bioavailability was greater than 80%in man [9]. A recent study where methimazole was administered both i.v. and p.0. to human subjects indicates virtually complete bioavailability and proportionality of area under the plasma concentration vs. time curve with drug dose [41].

IV. DISTRIBUTION

A. Pharmacokinetic Distribution Apparent volume of distribution (Vd) has been determined for both propylthiouracil and methimazole after p.0. and i.v. administration to animals and to man.



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For propylthiouracil, Sitar and Thornhill [13] reported a Vd of 0.35 L/kg in rats. Vd in cats after an i.v. dose has been determined to be 0.55 2 0.1 wkg and was not affected by hyperthyroidism [44]. In humans, Vd after parenteral administration has been reported as 0.30 wkg with no effect of hyperthyroidism [32,33]. Using median data from the report by Giles et al. [45], Vd of 0.40 wkg is calculated for propylthiouracil after an i.v. dose. After a p.0. dose of propylthiouracil between 2.5 and 18 mgkg in human subjects, Vd uncorrected for bioavailability (Vd/F), calculated from reported data, ranged from 0.34 to 1.96 W g (median 0.47 wkg) [22]. In euthyroid volunteers, Sitar and Hunninghake [23] reported V d F as 0.23 f 0.03 wkg. In a study of propylthiouracil disposition in hyperthyroid subjects after multiple doses, Sitar et al. [36] reported a median first dose Vd/F of 0.43 wkg and found that this disposition constant increased with chronic drug ingestion over a period of 6 months to 0.80 wkg. It is not known whether this change is confounded by altered drug bioavailability or whether it truly represents altered tissue distribution with chronic drug ingestion. Ringhand et al. [37] have reported a V d F of 0.43 k 0.02 Ukg after ingestion of a propylthiouracil solution and mean values ranging between 0.36 and 0.45 wkg when various commercial drug formulations were administered p.0. In a study on propylthiouracil disposition in pregnancy, V d F ranged from 0.18 to 0.64 Ukg [46]. Although these data are in reasonable agreement with other estimates after p.0. doses, the limited blood sampling of these patients necessitates caution in the interpretationof this estimate. In children, V d F after an oral dose was reported as 0.48 2 0.03 Likg, and was not changed with disease resolution [34]. From very limited data in older hypothyroid patients, Sitar et al. [38] calculated Vd/F for propylthiouracil ranging from 0.59 to 1.97 wkg. It is unlikely that this variation is due to age, since Kampmann et al. [40] found that Vd/F was not altered by aging in humans. The effect of severe hypothyroidism on drug absorption is a more likely mechanism to explain this observation [47]. For methimazole, Vd in rats after an i.v. dose has been reported as 0.67 L/kg [14]. In man, the only data on Vd after i.v. administration of methimazole was reported by Okamura et al. [41]. They determined a Vd of 2.1 2 0.3 Wkg in normal subjects and 1.9 f 0.3 Ukg in hyperthyroid patients. The initial report by Alexander et al. [9] suggests a Vd of less than total body weight, but these data should be interpreted cautiously since they measured only circulating radiolabel and not the parent drug. After methimazole is given p.0. to humans, mean Vd/F in four study groups ranged from 1.2 to 1.7 Ukg [41]. None of the other data reported corrected Vd/F for body weight. Thus, they cannot be compared to the data reported above.

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In conclusion, the kinetic distribution space for propylthiouracil is much less than for methimazole. These data suggest more extensive tissue binding for methimazole than for propylthiouracil and possibly explain the clinical observation of methimazole’s longer duration of action. Experimental evidence does not support a change in the size of this space in the hyperthyroid state.


B. General Tissue Distribution Of necessity, most data on tissue distribution result from studies in animals. In addition, there are considerable data on uptake of propylthiouracil and methimazole by the human thyroid gland. The earliest animal data on general distribution of propylthiouracil among the various tissues of the body indicate that early after an oral dose of 14C-labeled drug to female rats it was generally distributed throughout the body. No tissue accumulated label to a significantly higher concentration than plasma. Tissues with half or less the plasma concentration included brain, spleen, abdominal fat, eye, red marrow, yellow marrow, and skeletal muscle [48]. More data are available with respect to general tissue distribution of methimazole. After a dose of 14C-labeleddrug to female rats, there was a general distribution of radiolabel to most tissues early after the dose [48]. However, with this drug liver and kidney tended to accumulate more label than plasma. Marchant and Alexander [49] also observed that methimazole was concentrated by kidney and liver. Fewer tissues contained half or less I4C label after p.0. methimazole than after p.0. propylthiouracil. For methimazole, restricted distribution was seen only for abdominal fat within 4 h of the drug dose, and for yellow marrow at 4 h or later after the dose [48]. Skellern et al. [15] reported on tissue distribution of radioactivity after i.p. injection and p.0. doses of ‘‘C-labeled methimazole, but the earliest sampling time was 6 h after the dose. These data are in general agreement with those of Sitar [48], except that after i.p. administration at 6 h, the radiolabel was concentrated by the thyroid gland compared to plasma (1.4:l). These workers reporting data for time periods much longer than had other studies were able to show persistence of the label in liver, kidney, and lung to a greater degree than plasma up to 120 h after a single dose. Skellern et al. also examined tissue distribution of radiolabel after 5 and 10 repeated doses of methimazole to rats, but the pattern of relative tissue distribution was not different at 6 h after the last dose, except for accentuation of the thyroid:plasma concentration ratio for the radiolabel (2.4:l after 10 p.0. doses and 7:l after 5 i.p. doses). There is no explanation for the apparent difference in tissue:plasma ratio related to route of drug administration. The


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only other comparable data related to an i.p. dose of "S-labeled methimazole to rats [50].These data are in general agreement with those from the 14C-labeled methimazole studies, except that they also were able to demonstrate concentration of 3sSby the thyroid gland. At 1 h after the i.p. dose, there was also some concentration of "S by lung, adrenals, spleen, and muscle with tissue concentration in excess of plasma maintained only by the adrenals at later times.

C. Thyroid Gland The earliest data indicating the possible concentration of propylthiouracil by the thyroid gland were reported by Marchant et al. [51] for both rat and human tissue. Marchant and Alexander [49] next demonstrated methimazole accumulation in the thyroid gland of rats treated for 4 days with this drug. Marchant et al. [52] reported that rat thyroid gland accumulated radiolabel after doses of propylthiouracil and methimazole. They also demonstrated this phenomenon in normal human thyroid tissue, but not in thyroid neoplasms. After a dose of carbimazole, they found that most of the radiolabel in the thyroid gland was associated with methimazole. Concentration of methimazole by human thyroid gland was confirmed in a further study by Lazarus et al. [53]. These investigators also reported that human thyroid gland concentrated "S after a dose of radiolabeled propylthiouracil,but they did not characterize the chemical nature of the label. Accumulation of methimazole by the rat thyroid gland has also been confirmed recently by radioimmunoassay after drug ingestion in drinking water [30]. Marchant et al. [54] have also shown that the human fetal thyroid concentrated radiolabel after doses of radioactive propylthiouracil, methimazole, or carbimazole to pregnant women undergoing therapeutic abortions. Accumulation of propylthiouracil and methimazole by the thyroid gland is not directly dependent on the anion trap in the mouse [55, 561. In the rat, increasing iodide uptake increased total 35Sand propylthiouracil in the thyroid gland. However, as the dose of iodide increased, an increasing proportion of thyroid radioactivity was not parent drug [57]. These workers also reported that methimazole oxidation by rat thyroid gland to 3sS04increased with increasing iodine intake, but there was no correlation of methimazole oxidation to sulfate with total thyroidal iodine content [58]. Thus, the apparent concentration of radiolabel by the thyroid gland must be interpreted with caution with respect to whether this represents accumulation of unchanged drug and/or metabolites.

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D. Protein Binding Sitar and Thornhill [13] reported that propylthiouracil was 56.5 f 1.1% bound to plasma proteins in Sprague-Dawley rats, even though it has a low ch1oroform:water partition coefficient at physiological pH, 0.69 [48]. Kampmann et al. [59] reported that propylthiouracil was 80% bound to human serum proteins. This finding was confirmed by Giles et al. [45] and Taurog and Dorris [ 191, who reported protein binding to circulating plasma proteins of 81.8% and 82%, respectively. Cooper et al. [29] reported that propylthiouracil was bound 67.2 ? 5.5% to plasma proteins and that the binding was predominantly to albumin. Kampmann and Mulholm Hansen [60] reported that propylthiouracil was bound predominantly to albumin in man, 76.2 f 0.3% in euthyroid and 76.4 ? 0.4% in hyperthyroid subjects. They suggested the presence of two binding sites and demonstrated displacement by acetylsalicyclic acid, warfarin, and pheny Ibutazone. Sitar and Thornhill [14] reported that methimazole was bound 5.1 f 1.0% to plasma proteins of Sprague-Dawley rats. Taurog and Dorris [19] reported 10% binding of methimazole to rat serum proteins. Skellern et al. [43] and Johansen et al. [61] could not demonstrate serum protein binding of methimazole in humans. Taurog and Dorris [19] reported that methimazole was bound 8% to human serum protein. This reduced binding of methimazole compared to propylthiouracil occurred even though the ch1oroform:buffer partition ratio for methimazole at physiological pH was 3.3 [48], more than four times greater than for propylthiouracil. These data suggest that protein binding of propylthiouracil and methimazole is not primarily dependent on lipophilicity.

E. Formed Elements of Blood Early studies in rats showed restricted access of radiolabel to red blood cells after doses of propylthiouracil or methimazole, the effect being more striking for propylthiouracil [48]. Restricted access of radiolabel to red blood cells in rats has also been reported by Skellern et al. [15] and Marchant et al. [50], but the chemical nature of radiolabel was not determined in any of these studies. Lam and Lindsay [62] reported that phagocytizing polymorphonuclear leukocytes accumulated radiolabeled propylthiouracil8-10 times faster than resting cells. Subsequently, Shewring and Lazarus [63] reported that "S-labeled methimazole was not concentrated by peripheral blood lymphoctes from


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euthyroid rats or humans. Weetman et al. [64] demonstrated that human monocytes and human and rat macrophages accumulated methimazole in vitro. It is interesting to speculate that this accumulation of thioamide drugs might be related to their hematologic toxicity [65-67]. The low incidence of this side effect suggests the possibility of a pharmacogenetic mechanism.


F. Placental Transfer Fetal toxicity due to ingestion of thioamide drugs in pregnancy is a longstandingconcern. Marchant et al. [54] demonstrated that placental transfer of radioactivity was rapid after i.v. administration of methimazole,carbimaz'ole, or propylthiouracil to rats. There appeared to be restricted placental transfer of propylthiouracil. Human data in this same report appeared to confirm the findings in pregnant rats. Subsequently,disposition of propylthiouracil has been studied during human pregnancy, and limited data indicate that it can be used effectively without apparent harm to the developing fetus [46].

V. EXCRETION A. Urine

Desbarats-Schonbaum et al. [12] reported the presence of at least three propylthiouracil metabolites in guinea pig urine and a very small amount of unchanged drug; they did not report on the proportion of the dose excreted by this route. Sitar and Thornhill [13] determined that urinary excretion in rats represented 75-90% of the 20 mg/kg administered dose; only 9-15% of the dose was identified as unchanged propylthiouracil. Lindsay et al. [16] noted that about 72% of the administered dose of ''C-labeled and 65% of 35S-labeled propylthiouracil was excreted in 24-h urine. After a dose of approximately 6 m a g , they identified 27-30% as unchanged drug in urine. Taurog and Dorris [191 used high performance liquid chromatography to assist in isolating and identifying urinary propylthiouracil and metabolites from rats and a single human subject. They reported 40% of a dose in 6-h rat urine after 0.3-1.7 m a g i.p. administration. They identified 12% of the dose as unchanged drug. In their single human subject who received a 50-mg tablet and tracer 35S-labeled propylthiouracil, less than 1%of the drug was excreted unchanged in the 23-h urine specimen. Thus, in all species so far studied propylthiouracil appears to


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undergo significant metabolism before urinary excretion. This observation confirms the previous report by Giles et al. [45] that in healthy male humans 0.8-2% of an i.v. dose of propylthiouracil was excreted unchanged in urine up to 24 h. Sitar and Thornhill [14] reported that 77-95% of 20 mgkg doses of methimazole was excreted in rat urine and 1421% represented unchanged drug. Skellern et al. [151 indicated that their studies in rats demonstrated urinary excretion of 73-90% of a dose of methimazole with 6 7 % as unchanged drug after an i.p. dose of 3 mgkg. Okamura et al. [41] reported that 5.5-8.5% of 10-30 mg doses of methimazole was excreted unchanged in the urine of euthyroid and hyperthyroid humans. Thus, as for propylthiouracil, the majority of an administered dose appears to be metabolized and only a small fraction appears unchanged in urine.

B. Breast Milk Low et al. [65] reported radiolabel in human breast milk after doses of carbimazole or propylthiouracil, but this represented less than 1%of the administered dose. They did not identify the chemical nature of the radiolabel. Soon after, Kampmann et al. [59] reported that less than 0.03% of a propylthiouracil dose was excreted unchanged in human breast milk. Johansen et al. [61] reported that methimazole is excreted in human breast milk with a mi1k:serum ratio of 0.98. However, only 0.14%of the administered dose was excreted unchanged within 8 h of the dose. In conclusion, very little drug is excreted in breast milk after ingestion of these antithyroid drugs by lactating women.

C. Bile and Feces Primarily animal data are available with respect to excretion of thioamide drugs by these routes. Sitar and Thornhill [13] found 14% of an oral dose of propylthiouracil in rat bile up to 10 h after a 20 mgkg oral dose; none of the radioactivity was associated with unchanged drug. Papapetrou et al. [69] found about 8%of the dose in rat bile up to 5 h after i.v. administration. Lindsay et al. [16] reported 16%of a propylthiouracil dose in rat bile up to 6 h after a 6 mgkg dose with about 1%identified as unchanged drug. In two rats, Taurog and D o m s [19] reported that 17-20% of a dose was excreted in bile up to about 7 h. Sitar and Thornhill [13] reported that only 1.5% of a propylthiouracildose



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was found in feces. Thus, the possibility of enterohepatic circulation of propylthiouracil is indicated. Sitar and Thornhill [141 reported that about 10%of a 20 mgikg oral dose of methimazole was excreted in rat bile up to 10 h after the dose. In two rats, Taurog and Doms [19] reported that 32-35% of an i.v. dose of methimazole was excreted in rat bile up to 7 h after the dose, and they found 1.5-1.8% as unchanged drug. Skellern et al. [15] reported 443% of radiolabel in rat feces after 3 mgikg i.p. doses. Sitar and Thornhill [14] found only 1.5%of the I4C radiolabel in feces up to 48 h after methimazole doses to rats. Thus, with methimazole evidence for enterohepatic circulation is also present. The only human data were reported by Alexander et al. [9], who indicated that only 3%of "S-label was excreted in feces after a dose of propylthiouracil or methimazole. However, for neither of the two thioamide drugs has a definitive experiment been performed to confirm that enterohepatic circulation occurs.

VI. METABOLISM The first evidence for metabolism of propylthiouracil and methimazole was provided by Alexander et al. (91. This evidence was based on urinary radioactivity after doses of '%-labeled drug to two hyperthyroid patients. Pharmacokinetic Disposition. Most data where specific assays have been used indicate that propylthiouracil is eliminated from the body more rapidly than methimazole. However, species differences exist. Thus, in man, the terminal disposition half-life for propylthiouracil in plasma ranges from 1 to 2 h [22,23,29,3240,45,46]. In rats, the half-life is about 4 h [13], 6-7 h in guinea pigs, 2-3 h in mice [12], and 1-2 h in cats [44]. Gardner et al. [70] observed lower serum propylthiouracil concentrations in the third trimester of pregnancy in humans, with cord serum concentrations higher than simultaneous maternal samples. However, kinetic distribution was uncorrected for body weight, and the explanation for this observation is not clear with respect to the influence of pregnancy and/or hyperthyroid state. For methimazole, terminal half-life for circulating drug is much more variable, with estimations in man of 2-5 h [43], 2-7 h [42], 4-7 h [5,71], and 14-20 h [41]. In rats, terminal circulating half-life has been reported as 4 h after a single dose [14], and 72 h after a week of treatment [30]. Details of the metabolic disposition of thioamide drugs are presented below.

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488 A. Propylthiouracil


1. Circulating Metabolites

Using high specific activity 3SS-labeledpropylthiouracil, Marchant et al. [51] found lower propylthiouracil concentrations in rat plasma than indicated by total circulating radioactivity. Up to 4 h after a dose of approximately 5 mgkg, less than 5% of circulating radioactivity was identified as sulfate by thin-layer chromatography, with an additional similar proportion of radioactivity as propylthiouracil glucuronide. In a similar study with lower specific activity of ''C-labeled propylthiouracil, Sitar and Thornhill [131did not detect circulating metabolites in the plasma after a 20 mgkg p.0. dose. Desbarats-Schonbaum et al. [22] detected propylthiouracil metabolites in guinea pig plasma after a p.0. dose of approximately 1 g k g of 35S-labeleddrug. These metabolites amounted to only a very small fraction of total circulating radioactivity, and their only conclusion was that none was determined to be sulfate. In mice, these workers detected only one circulating metabolite of propylthiouracil after an i.v. dose of approximately 250 mg/kg. Marchant et a]. [54] were unable to detect propylthiouracil metabolites in the serum of pregnant humans. Taurog and Dorris [19] identified 13-18% of circulating radioactivity as sulfate 5 h after 7 mgkg doses of radioactivity to rats. Less than 1% of circulating radioactivity was present as an unidentified metabolite. In conclusion, very little circulating radioactivity has been identified as metabolites of propylthiouracil after widely divergent doses to various species. 2. Tissue Metabolites Bremer and Greenberg [72] described a microsomal enzyme which transferred methyl groups from S-adenosylmethionine in several tissues. Kidney, lung, and liver exhibited highest activity; testis, spleen, and intestine had 1/10 to 113 of the activity of liver microsomes. This activity was identified from liver tissue of rat, mouse, rabbit, guinea pig, beef, and sheep and much less in chickens. Borchardt and Cheng [73] purified and characterized this thiol methyltransferase from rat liver. They described the distribution of cellular activity as 66% in microsomes, 21% in nuclei, 10%of mitochondria, and 3% in the cytosol. Brain profile of this enzyme was described as similar to liver. However, in heart tissue this enzyme had a higher mitochondria1 localization. This thiol methyltransferase was isolated and purified by Weisiger and Jakoby [74], who described the requirement of S-adenosylmethionine as the methyl donor. Methylation occurred with a large number of acceptor molecules including propylthiouracil. The K,,, was determined to be 1.0 mM with a V,,, of 6.4 nmol/min/mg. The significance of this metabolic pathway for the much



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lower drug concentrations seen after clinically relevant propylthiouracil doses is not known. Lindsay et al. [75,76] have shown that guinea pig liver microsomes catalyze the glucuronide conjugation of propylthiouracil and that the site of conjugation is most likely with the thiol functional group. Interestingly, this reaction was inhibited by methimazole, but the investigators were not able to demonstrate glucuronide conjugation to this inhibitor. Marchant et al. [51] identified four radioactive compounds in rat and human thyroid tissue after doses of "S-labeled propylthiouracil. These compounds included unchanged drug, sulfate, protein-bound radioactivity, and an additional unidentified metabolite. With very limited data from human thyroid gland, these investigatorssuggested that a concurrent dose of potassium iodide administered with propylthiouracil reduced propylthiouracil metabolism by the gland. Lindsay et al. [77] examined rat thyroid glands for propylthiouracil metabolites 6 h after a dose of ''C-labeled drug. They identified the major metabolite, which accounted for about half of the gland radioactivity as a sulfinic acid of the parent compound. The next most abundant radioactive substance was protein-bound propylthiouracil, which accounted for just over one quarter of gland radioactivity. Propylthiouracil and its sulfonic acid metabolite accounted for approximately 10%each of glandular radioactivity.A very small amount of propyluracil was detected, and the investigatorspresented evidence for the presence of a small amount of unstable metabolite, which they tentatively identified as a thiol sulfonic acid of propylthiouracil. Lang et al. [57] demonstrated metabolism of propylthiouracil by the rat thyroid gland. The rate of metabolism increased with dose of iodide, but the nature of metabolites was not determined. Hunter and Neal [78] showed that propylthiouracil decreased microsomal cytochrome P-450 in rat liver microsomes from phenobarbital and 3methylcholanthrene-inducedrats. This effect, reflected in decreased benzphetamine demethylation in both types of microsomes, was not produced by the oxygen analog, propyluracil. Propylthiouracil produced centrilobular necrosis of rat liver in phenobarbital-induced, but not 3-methylcholanthrene-induced, rats. Kariya et al. [79] demonstrated that 10 mM propylthiouracil competitively inhibited rat liver cytosol glutathione transferase activity by 25%. Propylthiouracil sulfoxide was a more potent inhibitor of glutathione transferase activity, since 10 mM concentration caused 80% enzyme inhibition. This inhibitory effect was noncompetitive. The significance of this observation with respect to clinically relevant doses is not known. Taurog and Dorris [19] could not detect metabolites of propylthiouracil in rat liver 5 h after a dose of 35S-labeleddrug.

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3. BUiary Metabolites Excretion of radiolabel into bile after a dose of propylthiouracil is reported to range from 8 to 16%[13,16,69]. Desbarats-Schonbaum et al. [12] observed propylthiouracil metabolites in guinea pig bile after a p.o.200 mg dose (approx. 670 m a g ) of %-labeled drug. They did not quantify the metabolites, but claimed that no %04or unchanged propylthiouracil was detected. Sitar and Thornhill [13] detected over the 10-h collection period two peaks in bile from female rats administered a dose of 20 m a g 14C-labeledpropylthiouracil. None of the activity was attributable to unchanged drug, and the major metabolite (13% of administered dose) was identified as a glucuronide conjugate of propylthiouracil. Chromatographiccharacteristicsof this glucuronideconjugate led these workers to conclude that the biliary glucuronideconjugate was not the same as the urinary conjugate. Papapetrou et al. [69] reported eight radiolabeled peaks in bile of rats receiving propylthiouracil and identified propylthiouracil glucuronide as the major component. Sulfate and unchanged drug were also identified in this excretion pattern. The most extensive studies of propylthiouracil in rat bile were conducted by Lindsay et al. [16]. These investigatorsinjected 1 mg propylthiouracil (approx. 6 mgkg) and high specific activity tracer I4C- or 3SS-labeleddrug. Biliary excretion was followed for 6 h after the dose. Several radiolabeled compounds were identified in this fluid, including three different glucuronide and tentatively three different S-conjugates. The major biliary excretion product was a glucuronide conjugate of propylthiouracil, representing approximately 7%of the administered dose; 0.9%was unchanged drug, and 0.6%radiolabeled sulfate. The fact that only a small amount of radioactivity is excreted in feces [131 suggests that there may be enterohepatic circulation of biliary excretion products. In conclusion, all studies performed thus far suggest that the major biliary metabolite in rats receiving propylthiouracil is a glucuronide conjugate. Unidentified metabolites in bile remain to be characterized.

4. Urinary Metabolites Desbarats-Schonbaum et al. [121 reported at least three propylthiouracil metabolites in guinea pig urine and a very small amount of unchanged drug. No radiolabeled SO, was detected by these investigators. Sitar and Thornhill [13] identified a minimum of five urinary radioactive peaks in rat urine after an oral dose of propylthiouracil. Excretion by this route represented 7540% of the administered dose. Of the total urinary radioactivity,9-15% of the administered dose was unchanged propylthiouracil, 4 0 4 8 % was a glucuronide of the parent drug, and 10-16% was partially characterized, but not completely identified.



49 1

From mass spectral data [48], it was speculated that this latter metabolite probably resulted from side chain oxidation of the propyl group. Lindsay et al. [16] noted that about 72% of the administered dose of I4C-labeledand 65% of 35S-labeledpropylthiouracil was excreted in 24-h urine. After a dose of approximately 6 m a g , they identified 30% of the dose as unchanged drug, 12%as a glucuronide conjugate of propylthiouracil, 2.5%as S-methylpropylthiouracil, 3.7% as propyluracil, and 4.5% as 35S0,. The near concordanceof urinary propyluracil and sulfate suggests that propyluracil is the main metabolite resulting from desulfuration of the administered drug. Very recently, Taurog and Dorris [19] used high performance liquid chromatography to assist in isolating and identifying urinary propylthiouracil metabolites from rats and from a single human subject. They found that 40% of a 0.3-1.7 mgkg i.p. dose was excreted in 6 h. In this 6-h urine, they identified 12% of the dose as unchanged drug, 13% as a glucuronide conjugate of the parent drug, and 3% as either sulfate or sulfite. In their single human subject who received a 50-mg tablet and tracer 35S-labeledpropylthiouracil, less than 1% of the drug was excreted unchanged in the 23-h urine specimen, 53% as a glucuronide conjugate of the parent drug, and 19%as sulfate or sulfite. These investigatorsclaimed that human urine exhibited fewer radiolabeled peaks than rat urine. As with the biliary metabolites, identification of urinary propylthiouracil metabolites remains incomplete. However, glucuronidation appears to be quantitatively the most important pathway of disposition for this drug in guinea pig, rat, and man. A summary of reported propylthiouracil metabolites is presented in Fig. 2.

B. Methimazole 1. Circulating Metabolites Sitar and Thornhill [141 reported that a metabolite of 14C-labeledmethimazole was present in rat plasma after i.v. and p.0. doses of 20 m a g . The metabolite was detected by thin-layer chromatography within 6 h of the p.0. dose and 8 h after the i.v. dose, but it was not identified. Skellern et al, [80] identified 3-methyl-2-thiohydantoinin plasma of humans 10 h after an i.v. methimazole dose. Taurog and Dorris [19] reported the presence of radioactive sulfate and two other unidentified metabolites in rat serum after methimazole doses. They provided some evidence that one of these serum metabolites was 3-methyl-2-thiohydantoin. Thus, after doses of methimazole to various species, there would appear to be more evidence for significant amounts of circulating metabolites than after a dose of propylthiouracil.


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FIG. 2. Structures of propylthiouracil metabolites in mammalian species for which there is published evidence: (1)propylthiouracil;(2)propylthiouracilS-glucuronide; (3) S-methylpropylthiouracil; (4) propyluracil; ( 5 ) sulfate; (6) sulfite; (7) propylthiouracil disulfide; (8) propylthiouracil thiosulfonicester; (9) propylthiouracil-2-sulfinicacid; (10) propylthiouracil-2-sulfonicacid.

2. Tissue Metabolites Poulson et al. [81] showed that pig liver microsomal amine oxidase catalyzed the conversion of methimazole to N-methylimidazole and sulfite. They demonstrated the requirement for 2 moles of NADPH and one mole of oxygen per mole of methimazole. Production of this metabolite was correlated with amine oxidase activity in liver microsomes from rat, rabbit, and guinea pig, with highest activity from pig and rabbit tissue. Low amine oxidase activity was also



493

demonstrated in lung and intestine. It has since been demonstrated that a purified flavin-containing monooxygenase from both rabbit lung and pig liver is capable of oxidizing methimazole. This capability was demonstrated by oxygen and NADPH utilization, but no metabolites were identified [82]. Prough and Ziegler [83] could not demonstrate that cytochrome P-450 was involved in methimazole oxidation by liver microsomes, but they did demonstrate type I1 spectral binding with methimazole concentrations greater than 5 mM. Methimazole did not inhibit ethoxyresorufin deethylase or biphenyl-4-hydroxylase in concentrations up to 1mM, but at this concentration, methimazole inhibited p-chloro-N-methylanilinedemethylation 20-30% and benzphetamine demethylation &7% in 3-methylcholanthrene induced rat liver microsomes. Lee and Neal [17] showed that rat liver rnicrosomes catalyzed the production of N-methylimidazole, but in contrast to the findings of Poulson et al. [81] and Prough and Ziegler [83], they claimed that this reaction was mediated by the cytochrome P-450 system. Lee and Neal cited as evidence the inhibition of the metabolic reaction by cytochrome P-450 antibodies. The apparent K,,, was reported as 18 mM, considerably in excess of tissue concentrations after therapeutic doses. However, N-methylimidazole was also formed in the absence of NADPH, indicating that if cytochrome-P450 is involved, it is not the only mechanism for formation of this metabolite. Lee and Neal [17] demonstrated alkylation of microsomes by radiolabeled methimazole, which when hydrolyzed in the presence of cyanide yielded free methimazole and thiocyanate. The K,,, for alkylation was lower with "S- than "C-labeled drug, but V,, was higher for 35S-labeledmethimazole. Alkylation was inhibited by carbon monoxide and cytochrome P-450 antibodies, again suggesting involvement of cytochrome P-450 in the metabolic reaction and probably the -SH functional group of methimazole. Microsomal binding of methimazole also occurred in the absence of NADPH, but the mechanism is unknown. Taurog and Doms [19] also found evidence for covalent binding of radioactivity to rat liver, but they did not identify the nature of the adduct. These data support the hypothesis that hepatotoxicity seen with methimazole could be mediated by alkylation of microsomal protein, since centrilobular necrosis of the liver occurs in phenobarbital-induced rats after methimazole and microsomal cytochrome P-450 is decreased in the presence of methimazole and NADPH [78]. The relative importance of amine oxidase compared to cytochrome P-450 in formation of N-methylimidazole remains to be demonstrated. Conn et al. (841 showed that ram seminal vesicle microsomes oxidize methimazole to N-methylimidazole. They implicated prostaglandin endo-


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peroxide synthetase as the responsible enzyme. This metabolic reaction was at least in part associated with protein binding of sulfur. Lee and Neal [17] also determined that 3-methyl-2-thiohydantoin was formed during incubation of methimazole with liver microsomes from male Sprague-Dawley rats. Lindsay et al. [85] reported that methimazole was not S-methylated by mouse kidney thiol methyltransferase. However, Weisiger and Jakoby [74] demonstrated that thiol S-methyltransferase purified from Sprague-Dawley rat liver of 1.4 mM and a V,, was active in the S-methylation of methimazole, with a K,,, of 2.0 nmol/min/mg enzyme. Although the enzyme was associated with the microsomal fraction, freezing of the tissue before enzyme purification liberated 30% of the enzyme activity in the 100,OOO x g supernatant. Skellern et al. [80] reported the isolation of 3-methyl-2-thiohydantoinfrom human thyroid tissue 10 h after methimazole ingestion by a hyperthyroid patient, but they provided no evidence that this metabolite was generated in the gland itself. Paterson et al. [86] reported that porcine thyroid peroxidase metabolized methimazole to methimazole disulfide. Subsequently Taurog et al. [20] reported that methimazole disulfide is the earliest appearing metabolite when "S-labeled drug is incubated with purified thyroid peroxidase from rats. This was followed by the appearance of sulfate or sulfite and another unidentified methimazole metabolite. Their assay was unable to distinguish sulfate from sulfite. Thus, the nature of the radiolabeled oxidized sulfur in their experiments could not be definitively determined. When the enzyme was incubated with 14C-labeledmethimazole, the major metabolite was reported to be N-methylimidazole. Thyroid glands from rats injected with "S-labeled methimazole contained only radiolabeled sulfate or sulfite as metabolites. This interpretation is tempered by their finding that other metabolites produced by thyroid peroxidase do not survive the homogenization procedure they used for the rat thyroid gland.

3. Biliary Metabolites Papapetrou et al. [69] described a glucuronide conjugate of a methimazole metabolite in rat bile. Sitar and Thornhill [14] identified in rat bile three radioactive compounds after doses of ''C-methimazole, one of which they identified as methimazole glucuronide, constituting 4% of the administered dose. One of the other peaks in rat bile was determined to be identical to a


495

urinary metabolite of methimazole. Paurog and Dor- ':i [ 191 described three biliary metabolites in rats after a dose C 35S-labeleddri'g. The minor peak was methimazole, and one of the major peaks a labile glwuronide metabolite of methimazole. They did not detect any rnethimazole ghcuronide.


4. Urinary Metabolites

Alexander et al. [9] reported three radioactive compounds in human urine after a dose of "S-labeled methimazole, and indicated that two of them were unchanged methimazole and inorganic sulfate. This study presents the first evidence for methimazole metabolism. Pittman et al. [87] used a colorimetric assay to identify chromogenic material in urine of human subjects receiving methimazole, but its qualitative nature was not determined. Sitar and Thornhill [14] identified in rat urine three radioactive compounds after 14C-labeledmethimazole, and identified them as parent drug (1421% of dose), methimazole glucuronide (3648% of dose), and an unknown metabolite designated M-1. Skellern et al. [151isolated six radioactive peaks from rat urine, but their data indicated that no more than 3% of the dose might be attributed to methimazole glucuronide. Their studies also suggested that this conjugate was labile, since incubation without glucuronidase released the same quantity of methimazole. None of the other urinary metabolites were identified in this study, but they found more urinary metabolites after p.0. than i.p. doses. Subsequently, Skellern and Steer [ 181 characterized some of these rat urinary metabolites as S-methylmethimazole, 1-methylimidazole, 3-methyl-2-thiohydantoin, and tentatively 3-methylhydantoin and 1-methyl-2-thiohydantoicacid, which was suggested to degrade to N-methylthiourea. However, all these metabolites accounted for less than 11% of the dose. Taurog and Doms [19] reported that the two most abundant metabolitesin rat urine were not susceptible to glucuronidase hydrolysis. These investigators were unable to detect 3-methyl-2-thiohydantoinin rat urine. Limited data from a single human subject were described as similar to that from rat urine. In patients receiving carbimazole, Skellern et al. [80] identified 3-methyl2-thiohydantoin as a urinary metabolite. They estimated that it accounted for about 3% of the dose. Twele et al. [88] identified after methimazole 2-mercapto-l-methyl-Smethylmercaptoimidazole in human and rat urine. They suggested that this metabolite could arise after N-oxidation to yield an intermediate susceptible to nucleophilic attack. This nucleophile was proposed to be glutathione, which


4%

SITAR

could then be degraded to a methylthio derivative. Twele et al. [88] also observed 3-methyl-2-thiohydantoin as a minor methimazole metabolite in rat urine and a trace metabolite in human urine. A summary of reported methimazole metabolites is presented in Fig. 3. Studies on the nature and amounts of methimazole metabolites are confounded by the fact that methimazole and its metabolites are unstable. Skellern and Steer [I81 observed that over short time periods solutions of methimazole are unstable, even at low temperature. These same investigators also reported that 3-methyl-Zthiohydantoin was unstable at alkaline pH and

FIG. 3. Structures of methimazole metabolites in mammalian species for which there is published evidence: (1)methimazole; (2) N-methylimidazole; (3) sulfate; (4) methimazole disulfide; (5) S-methylmethimazole; (6) methimazoleS-glucuronide; (7) 3-methyl-2-thiohydantoin; (8) 1-methyl-2-thiohydantoic acid; (9) N-methylthiourea; (10) 3methylhydantoin; (1 1) 2-mercapto-1methyl-5-methylmercaptoimidaole.


497


broke down to yield 1-methyl-2-thiohydantoic acid. Methimazole disulfide is unstable and decays nonenzymatically to yield methimazole and an unidentified metabolite described by Taurog et al. [20]. This instability of methimazole disulfide confirms the initial observation by Paterson et al. [83]. More research is required to confirm that after doses of methimazole the products isolated from biological sources in fact reflect metabolic activity and not artifacts of the isolation procedures.

C. Drug Metabolism in Thyroid Dystunction Vesell et al. [89] indicated that hyperthroidism shortened the plasma half-life of propylthiouracil and methimazole, while hypothyroidism lengthened the half-life for these drugs. Although this finding was partially supported in a subsequent study [36], no change in plasma clearance was demonstrable, and the possibility of altered kinetic distribution volume was advanced as the explanation for altered plasma half-life. This aspect of disease effect on drug disposition is rather controversial, and there is evidence both in support and against an effect of thyroid disease on drug metabolism [47, 90, 911.

VII. CONCLUSIONS From the published data propylthiouracil and methimazole exhibit considerable differences in disposition. Plasma protein binding is higher for propylthiouracil, and this may contribute to its more restricted kinetic distribution volume compared to methimazole. Both drugs are widely distributed to various tissues and cross the placenta. Urine represents the major route of excretion, and only very small amounts of the dose appear in breast milk or feces. Before being excreted, propylthiouracil and methimazole are extensively metabolized. Glucuronide conjugation appears to be the major metabolic pathway for propylthiouracil and is controversial with respect to the disposition of methimazole. Oxidative metabolism has been demonstrated for both drugs; more putative metabolites have been described for methimazole. Oxidative metabolism apparently is not limited to the classical mixed function oxidase system. However, the metabolism of both drugs is far from complete determination. Reported instability of methimazole and some of its metabolites indicates the distinct possibility of artifacts arising during isolation of putative metabolites from biological sources. The relationship of metabolism of thioamide drugs to their toxicity remains to be demonstrated.

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498

Acknowledgments


The author is grateful to the Medical Research Council of Canada, the United States Public Health Service, the Canadian Foundation for the Advancement of Clinical Pharmacology, and Le Conseil de la Recherche en Sant&du QuCbec for financial support of his research cited in the present manuscript.

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Agranulocytosis and antithyroid drugs.

Rethinking antithyroid drugs in pregnancy.

How antithyroid drugs work in Graves' disease.

Aplastic anemia associated with antithyroid drugs.

The mechanism of action of the thioureylene antithyroid drugs.

Predicting relapse of Graves' disease following treatment with antithyroid drugs.

The effects of antithyroid drugs on intercellular mediators.

Mechanism of action of thioureylene antithyroid drugs: factors affecting intrathyroidal metabolism of propylthiouracil and methimazole in rats.

Breastfeeding and antithyroid drugs: a view from within.

Adverse effects related to antithyroid drugs and their dose regimen.

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Factors affecting drug-induced liver injury: antithyroid drugs as instances.

Antithyroid drugs and Graves' disease: a prospective randomized evaluation of the efficacy of treatment duration.

The mechanism of action of synthetic antithyroid drugs: iodine complexation during oxidation of iodide.

Correlation of HLA and thyroid antibodies with clinical course of thyrotoxicosis treated with antithyroid drugs.

Analysis of antithyroid drugs in surface water by using liquid chromatography-tandem mass spectrometry.

Spleen-specific development of germinal centers in rats treated with antithyroid drugs.

Best practice for the pharmacological management of hyperthyroid cats with antithyroid drugs.

Remission of Graves' disease with hyperthyroidism by a combination of glucocorticoids and antithyroid drugs.

Antithyroid drugs and release of inflammatory mediators by complement-attacked thyroid cells.

Semi-synthesis of thioamide containing proteins.

Congenital anomalies in children exposed to antithyroid drugs in-utero: a meta-analysis of cohort studies.

An overview on the proposed mechanisms of antithyroid drugs-induced liver injury.