Summary
Studies of antithyroid drug pharmacokinetics suffer from the lack of simple and sensitive methods for the measurement of these drugs in biologic fluids. This is reflected by most of the data available at present. From a critical review of these studies, the following conclusions emerge:
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1)
Absorption of methimazole and carbimazole is subject to considerable interindividual variability, which is more pronounced for methimazole than for carbimazole.
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2)
Propylthiouracil, but not methimazole, is bound to plasma proteins.
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3)
After administration of carbimazole, only methimazole can be detected in serum and thyroid tissue. Conversion of carbimazole to methimazole appears to be an enzymatic process. Methimazole plasma levels are lower after carbimazole administration than after equal amounts (on a weight basis) of methimazole; 10 mg carbimazole are equivalent to 6–7 mg methimazole.
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4)
Methimazole and propylthiouracil plasma levels decrease with time according to first-order kinetics. Serum half-life of propylthiouracil is about 1 h, half-life of methimazole is 2–6 h.
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5)
Antithyroid drugs are concentrated by the thyroid gland. This accumulation is inhibited in iodine deficiency in animals. Inhibition of iodide organification is dependent on intrathyroidal rather than plasma concentration of antithyroid drugs.
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6)
Intrathyroidal metabolism of antithyroid drugs involves binding to thyroglobulin and stepwise oxidation. The main metabolite of propylthiouracil is PTU-SO2H. A metabolite of methimazole, methylthiohydantoin, can be detected in plasma and urine.
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7)
Propylthiouracil is rapidly coupled to glucuronic acid. A significant proportion of antithyroid drugs and their metabolites is excreted into bile and later reabsorbed (enterohepatic circulation). Fecal excretion is very low. In urine, small amounts of unchanged drugs are excreted together with glucuronides, methyl derivatives (only PTU) and unidentified metabolites.
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8)
In pregnancy, methimazole half-life appears to be shortened. Methimazole and propylthiouracil can cross the placenta and are detected in the fetal circulation and thyroid. Concentrations in breast milk are very low, especially for propylthiouracil.
Zusammenfassung
1. Untersuchungen der Pharmakokinetik von Thyreostatika sind durch das Fehlen einfacher und empfindlicher Bestimmungsmethoden für diese Pharmaka in biologischen Flüssigkeiten erschwert.
2. Die Resorption von Carbimazol und — besonders — Methimazol ist erheblichen interindividuellen Schwankungen unterworfen.
3. Propylthiouracil, aber nicht Methimazol wird an Plasmaproteine gebunden.
4. Nach Gabe von Carbimazol ist nur Methimazol im Serum, Urin und Schilddrüsengewebe nachweisbar. Die Konversion von Carbimazol zu Methimazol scheint enzymatisch gesteuert zu werden. Die Methimazol-Plasmaspiegel sind nach Gabe von Carbimazol niedriger als nach Gabe einer gleichen Menge von Methimazol. 10 mg Carbimazol sind äquivalent zu 6–7 mg Methimazol.
5. Verteilung und Elimination von Methimazol und Propylthiouracil können durch ein Ein-Kompartment-System mit Eliminationsweg 1. Ordnung beschrieben werden. Die Plasmahalbwertszeit von Propylthiouracil beträgt etwa 1 h, die von Methimazol 2–6 h.
6. Thyreostatika werden in der Schilddrüse angereichert. Diese Anreicherung wird bei Labortieren durch Jodmangel gehemmt. Die Hemmung der Jodidorganifikation hängt mehr von der intrathyreoidalen als der Plasmakonzentration der Thyreostatika ab.
7. In der Schilddrüse werden die Thyreostatika schrittweise oxidiert und teilweise an Thyreoglobulin gebunden. Der Hauptmetabolit von PTU ist PTU-SO2H. Ein Methimazolmetabolit, das Methylthiohydantoin, kann im Plasma und im Urin nachgewiesen werden.
8. Propylthiouracil wird rasch an Glucuronsäure gekoppelt. Ein beträchtlicher Teil der Thyreostatika und ihrer Metabolite wird mit der Galle ausgeschieden und später reabsorbiert (enterohepatischer Kreislauf). Die faekale Ausscheidung ist sehr niedrig. Im Urin erscheinen geringe Mengen der nicht metabolisierten Substanzen zusammen mit Glucuroniden, Methylderivaten (nur bei Propylthiouracil) und unidentifizierten Metaboliten.
9. In der Schwangerschaft ist die Halbwertszeit von Methimazol verkürzt (nach vorläufigen Daten). Methimazol und Propylthiouracil durchqueren die Plazentaschranke und können im fetalen Blut und in der fetalen Schilddrüse nachgewiesen werden. Die Konzentrationen in der Muttermilch sind sehr gering, besonders bei Propylthiouracil.
10. Über die Änderungen der Thyreostatika-Pharmakokinetik während der Behandlung einer Hyperthyreose gibt es bisher nur unzureichende Daten.
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Benker, G., Reinwein, D. Pharmacokinetics of antithyroid drugs. Klin Wochenschr 60, 531–539 (1982). https://doi.org/10.1007/BF01724208
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DOI: https://doi.org/10.1007/BF01724208
Key words
- Antithyroid drugs
- Methimazole
- Carbimazole
- Propylthiouracil
- Pharmokinetics
- Absorption
- Metabolism
- Excretion
- Placental Transfers
- Pregnancy