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Methimazole: An Anti-Thryoid Agent

Methimazole, also known by its brand name Tapazole, is an anti-thyroid agent commonly used in
the treatment of hyperthyroidism. This paper will provide a brief overview
of the important aspects of the drug in a medical, pharmacological, and
molecular sense. The drug itself was discovered by E.B Astwood and M.M
Stanley, two prominent thyroid researchers the former of which to, the
discovery and development of the radioactive iodine uptake test, is
attributed. As indicated by the drug class, the drug targets a gland in the
body known as the thyroid, which has several functions, namely the
production of a set of important regulatory hormones, which will be
discussed further later. This organ is also fairly susceptible to imbalances
Figure 1. Skeletal structure of
which leads to various thyroid diseases, including hyperthyroidism, for
Methimazole.
which methimazole is prescribed. There are several sites and processes
within the thyroid that are commonly affected by these diseases and as such serve as potential drug
targets. Methimazole primarily acts against an enzyme in the synthesis pathway of the thyroid, allowing
for down regulation of that synthesis pathway in order to reduce overall thyroid hormone levels in the
body. The pharmacokinetics and pharmacodynamics of methimazole are fairly well understood, given that
the drug was discovered in 19491. These facets, as well as the common side effects, similar drugs within
this drug class, and potential for further development of the drug are also to be discussed.
To most effectively grasp how methimazole works, there must also be at least a basic understanding of the
thyroid. The gland itself is butterfly shaped, comprised of two lobes located behind the trachea. The
glands primary interaction with other parts of the body comes in the form of its relationship with the
pituitary gland, which releases thyroid-stimulating hormone, the primary regulation factor for the thyroid.
The various processes within the thyroid are primarily iodine dependent, and so the gland is a site for
major iodine uptake in the body. It uses this iodine in order to produce triiodothyronine, or T3, and
thyroxine, T4, two hormones, whose nomenclature just so happens to signify the number of iodine atoms
present in their structures. These hormones serve as growth and transcription factors elsewhere in the
body in conjunction with other proteins and enzymes. The thyroid also produces a hormone called
calcitonin, a blood-calcium level up regulator.
Obviously, the gland itself is not the issue, but rather what goes wrong with it, and so an
understanding of thyroid diseases is also useful in understanding methimazole. The first group of diseases
relates to thyroid hormone synthesis levels. If these hormones are too high or are being overproduced, it is
called hyperthyroidism, and is associated with Graves disease and thyroid toxicosis (poisoning). The
opposite case is hypothyroidism, which is associated with Hashimotos thyroiditis, an auto-immune
disorder. More physical ailments of the gland are also possible, as is the case with goiter, or an
enlargement of the larynx due to swelling or inflammation of the thyroid. Many of these are symptoms
over bigger diseases and as such are seen together. These larger umbrella diseases also share many
common areas of effect and share symptoms outside of those listed. As with any living and replicating
tissue, there is also the potential for the development of thyroid cancer. Any of these conditions can also
lead to secondary conditions, such as cretinism, which is stunted or retarded growth due to thyroid
hormone deprivation during developmental stages of life.

1 Methimazole (IARC Summary & Evaluation, Volume 79, 2001). (2001, September 25). Retrieved May 13, 2015, from
http://www.inchem.org/documents/iarc/vol79/79-01.html

Now with a basic understanding of the thyroid and those diseases that affect it, the sites within the
gland that are viable for drug targeting can be explored. Figure 2 below, gives a basic overview of the
thyroid hormone synthesis pathway and names some of those structures that can be targeted. Firstly there
is the iodine uptake mechanism for the thyroid that exists in the form of the Na +/I- symporter.
Interestingly, the glands follicles compartmentalize many of the processes as can also be seen in the
figure. For example the precursors for thyroid hormones, namely iodine and thyroglobulin are produced
in the follicular cell, but are not activated until they are transported into the follicular colloid. A fair few
of the other drug targets in the thyroid exist in this follicular colloid, where the iodine and thyroglobulin
are processed. To list these, there is the oxidation of iodine, the iodination of thyroglobulin, and the
conjugation of the tyrosyl residues. Steps further downstream including the proteolysis of the conjugated
residues, or uptake of the finished thyroid hormones by other tissues, may also be of interest, but the one
to be focused on, as it is the target of methimazole, is the enzymatic oxidation of I - to I0 via thyroid
peroxidase.

Methimazole has been shown to have a somewhat two-fold effect in its inhibition of thyroid
peroxidase (TPO). The first is inactivation of the enzyme, and the second is to act as an iodine sponge as
shown by Engler et al.2 It does these separately, though both presumably accomplish its intended in vivo
function. As to the first mode of action, methimazole has been shown to inactivate TPO in both its
oxidized and reduced states, though its effects were greater on the former. This was tested by the inclusion
or exclusion or hydrogen peroxide in a mixture with a known concentration of methimazole and the
enzyme. Spectrophotometry in the 380-440nm range, was used to indicate exactly which species were
reacting in a given mixture. One of the primary discoveries was the methimazole formed a complex with
the heme group of the TPO leading to a notable absorbance in the range specified above. As such,
increases and decreases in this absorbance were examined in the mixtures as a potential result of
interactions between methimazole and the other species in solution in later tests. Other mixtures were also
tested using these methods that included or excluded iodine, in order to test how the drug reacted in the
2 Engler, H., Taurog, A., & Nakashima, T. (1982). Mechanism of inactivation of thyroid peroxidase by thioureylene drugs. Biochemical
Pharmacology, 31(23), 3801-3806. doi:00006-2952/82/23380-06

presence of species that is readily available in the intended in vivo site. The results showed that in the
presence of iodine, the inactivation of both forms of thyroid peroxidase, reduced and oxidized, was
prevented. This protective effect of iodine is a result of interactions between methimazole and elemental
iodine, and these reactions may explain the sponge effect methimazole appears to have on iodine. The
exact byproducts of these interactions are not yet known, but it is hypothesized that a number of monoand di-cationic species are formed from monomers made up of two methimazole molecules connected
by a disulfide bond, which eventually give way to individual methimazole disulfide dimers 3. The structure
of the cationic species is highly dependent on the polarity of the solution in which they are formed, which
may influence further interactions within the thyroid as well as how these compounds are treated in the
body. Regardless of the nature of the interactions, usage of the iodine
by methimazole means less substrate for the enzyme. All of the above
tests also examined the function of another commonly used antithyroid agent, propylthiouracil (PTU, Figure 3). PTU was shown to be
markedly less effective in essentially all cases, though it did serve as a
useful comparison tool. One further set of tests was conducted on
methimazole and PTU to check for inhibition of TPO with a nonnative substrate, in this case guaiacol. The results showed that both
methimazole and PTU acted as competitive inhibitors for the guaiacol
Figure 3. Skeletal Structure of propylthiouracil
binding, though it is not clear if the binding site for guaiacol is the exact same as it is for iodine. To
summarize these molecular findings, methimazole is presumed to be a dual-functioning competitive
inhibitor of the thyroid peroxidase enzyme that causes inactivation in the absence of iodine and down
regulation in the presence of iodine.
The above examination of the molecular basis of inhibition give a fairly good indication of the structure
activity relationship for methimazole as well. Both it and PTU are small molecules so there is not much
variability to the pharmacophore, also indicated by the fact that there are no commonly used derivatives
of methimazole. Both methimazole and PTU contain an imidazole ring with thione substitutions. The
sulfur is clearly important as indicated previously due to the formation of those disulfide species. The
imidazole rings likely help provide stabilization as well as improvement of the chemistry at that site.
Methimazole and PTU do differ in some notable ways, which accounts for the differences in their
function both with respect to the thyroid peroxidase and the rest of the body. Most notably PTU has a
carbonyl functionality on the imidazole ring as well, which may account for its ability to interact with 5`iodinase, a peripheral effect not seen with methimazole.
Moving away from the molecule details of the drug, some of the larger pharmacological and
pharmacokinetic details are outlined below. Methimazole is absorbed fairly well by the body, primarily
through an oral dose. Literature values for the oral bioavailability of methimazole show it to be upwards
of 90%4. Other methods of dosing are not well tested in humans, though intravenous and intraperitoneal
injections have been used in animal studies. The actual movement from the digestive tract to the
bloodstream occurs after oxidation of the compound in the intestines, the pH of which are ideal for this.
Absorption curves for the drug indicate the potential for two points of uptake in the intestines, though this
3 Aragoni, M., Arca, M., Demartin, F., Devillanova, F., Garau, A., Isaia, F., . . . Verani, G. (2002). Anti-Thyroid Drug Methimazole:

X-ray
Characterization of Two Novel Ionic Disulfides Obtained from Its Chemical Oxidation by I 2. J. Am. Chem. Soc. Journal of the American
Chemical Society, 124, 4538-4539. doi:10.1021/ja012731k

4 Preissner, S., Kroll, K., Dunkel, M., Senger, C., Goldsobel, G., Kuzman, D., . . . Preissner, R. (2009). SuperCYP: A comprehensive database on
Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Research, 38(D237-D243).
doi:10.1093/nar/gkp970

is far more pronounced in the prodrug form of methimazole, Carbimazole. It takes approximately 1 hour
to reach peak plasma concentrations in most patients 5, after which it distributes throughout the body,
though most of it aggregates in the thyroid. The half-life of the drug in circulation ranges from 3-5 hours.
Metabolism of the drug is handled primarily by the cytochrome P450 enzymes, though which of these is
responsible for the actual degradation and which the drug simply has other interactions with is unclear.
Methimazole is hypothesized to interact with all of the CYPs, though it is known to interact (as an
inhibitor) with: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4. Methimazole is excreted renally, and a
typical dose of 5-30 mg exits the body within at least 12 hours, though it can be longer depending on
patient liver function and other drug interactions.
As to the medicinal information on methimazole, the main side effects associated with this drug are
common to many drugs and include things such as rash, itching, upset stomach, abnormal sensations,
drowsiness and dizziness. These are generally not serious though any adverse side effect is generally
cause for reconsideration of the prescription. The more concerning side effects associated with use of
methimazole relate to decreased white blood count (leukopenia, esp. neutropenia) and decreased platelet
count (thrombocytopenia). Agranulocytosis is a very serious side effect of methimazole in which the level
to which the concentration of white blood cells, in particular granulocytes which include neutrophils,
decreases below 500 cells/mm3 blood. This results in severe immunosuppression and puts patients at high
risk for infection. Other serious concerns arise due to the high level of CYP promiscuity exhibited by
methimazole. Patients on medications such as: blood thinners (Warfarin), Tamoxifen, heart medications
(digoxin), and certain supplements are advised not to take methimazole due to these interactions. Most
commonly, because methimazole inhibits these enzymes, doses of these drugs linger in the body longer so
proper dosing becomes harder to determine. Since its introduction in 1949, methimazole has also been
highly regulated in its use in pregnant or nursing mothers due to the ability of the drug to be secreted in
breast milk. The effect of infant thyroid development has always been a concern, as changes to the rate or
manner in which the thyroid develops can lead to other serious developmental issues, most notably
decreased brain function. Studies however, have shown that the levels of methimazole required to have
infants show any signs of impacted development are high 6. There has also been shown to be interactions
between methimazole and the melanin synthesis pathway7.
Further development of novel anti-thyroid agents does not appear to be a major area of research though
certain aspects of their function may be of interest. Development of a better understanding of the exact
interactions that occur between methimazole and other anti-thyroid drugs and thyroid peroxidase may
provide more insight into the molecular function of the thyroid. The interaction between methimazole and
the melanin synthesis pathway has led some researchers to believe methimazole may serve as a lead
compound for the synthesis of novel skin depigmentation compounds. While the development of anti5 Skellern, G., Knight, B., Low, C., Alexander, W., Mclarty, D., & Kalk, W. (1980). The pharmacokinetics of methimazole after oral
administration of carbimazole and methimazole, in hyperthyroid patients. British Journal of Clinical Pharmacology, 137-143.

6 Azizi, F., Khoshniat, M., Bahrainian, M., & Hedayati, M. (2000). Thyroid Function and Intellectual Development of Infants Nursed by
Mothers Taking Methimazole. The Journal of Clinical Endocrinology & Metabolism, 85(9), 3233-3238. Retrieved May 8, 2015, from
press.endocrine.org

7 Kasraee, B., Hugin, A., Tran, C., Sorg, O., & Saurat, J. (2004). Methimazole Is an Inhibitor of Melanin Synthesis in Cultured B16 Melanocytes.
J Invest Dermatol Journal of Investigative Dermatology, 122, 1338-1341. doi:10.1111/j.0022-202X.2004.22509.x

All images courtesy of commons.wikimedia.org

thyroid agents maybe at an end for now, the work done on these compounds still holds promise for
discoveries in other areas.