Propylthiouracil
| Evidence Level: L4 | Predicted Indications: 3 |
Table of Contents
- Propylthiouracil
- Propylthiouracil: From Hyperthyroidism to Resistance to Thyroid Hormone (TRβ Mutation)
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Propylthiouracil: From Hyperthyroidism to Resistance to Thyroid Hormone (TRβ Mutation)
One-Sentence Summary
Propylthiouracil is a thionamide antithyroid agent, historically used to treat hyperthyroidism, including Graves’ disease and thyrotoxicosis. The TxGNN model predicts it may be relevant to Resistance to Thyroid Hormone due to a Mutation in Thyroid Hormone Receptor Beta (TRβ), but this direction is currently supported only by 6 case report/mechanistic publications, with no registered clinical trials for this specific indication.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Hyperthyroidism / Graves’ disease (thyrotoxicosis) — inferred from literature evidence; no formal regulatory indication text available for the UK |
| Predicted New Indication | Resistance to Thyroid Hormone due to a Mutation in Thyroid Hormone Receptor Beta |
| TxGNN Prediction Score | 99.66% |
| Evidence Level | L4 |
| UK Market Status | Not marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available for propylthiouracil in this evidence pack. Based on known pharmacology, propylthiouracil is a thionamide-class antithyroid agent that inhibits thyroid peroxidase, thereby blocking thyroid hormone synthesis, and additionally inhibits peripheral conversion of T4 to T3. Its efficacy in hyperthyroidism and Graves’ disease is well established clinically, as reflected repeatedly in the supporting literature (e.g. PMID 31345521, PMID 25185644).
Resistance to Thyroid Hormone (RTH) due to TRβ mutations is a related but distinct endocrine disorder: patients present with elevated circulating thyroid hormone (T3/T4) but reduced tissue responsiveness due to a defective receptor, rather than true glandular overproduction. Because the biochemical presentation (raised thyroid hormone levels, variably suppressed TSH) can mimic thyrotoxicosis, patients with RTH have on occasion been misdiagnosed and empirically treated with antithyroid drugs, including propylthiouracil — this is explicitly documented in the evidence pack (PMID 10724359: a patient with RTH “was previously treated with propylthiouracil based on the diagnosis of thyrotoxicosis”; PMID 3097618: RTH patients “treated with propylthiouracil…for suspected thyrotoxicosis”).
This shared biochemical axis — thyroid hormone synthesis and receptor-mediated signalling — provides a plausible, though indirect, mechanistic rationale for the TxGNN prediction. However, the existing literature describes propylthiouracil use in RTH primarily as a historical misdiagnosis/mistreatment scenario rather than as an intended therapeutic strategy, which should temper enthusiasm for this repurposing candidate.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 18561095 | 2009 | Case report | Exp Clin Endocrinol Diabetes | TRβ gene mutation (P453A) identified in a Turkish family with RTH (mother and son) |
| 12201835 | 2002 | Case report | Clinical Endocrinology | TRβ mutation (M313T) family; infant with neonatal thyrotoxicosis and maternal infertility linked to RTH |
| 10724359 | 1999 | Case report | Endocrine Journal | De novo TRβ mutation (L330S) in a Thai woman with RTH; patient had previously received propylthiouracil for suspected thyrotoxicosis, with goitre worsening |
| 14684607 | 2004 | Preclinical | Endocrinology | Mouse model shows mutant TRβ (Δ337T) acts as a dominant-negative in cardiac tissue, altering TH responsiveness |
| 22919057 | 2012 | Preclinical | Endocrinology | Thrb(PV/PV) mouse model with homozygous TRβ mutation spontaneously develops follicular thyroid carcinoma; role of TSH explored |
| 21909131 | 2012 | Preclinical | Oncogene | Dominant-negative TRβ mutant (PV) mouse model links thyroid hormone signalling to tumour cell proliferation in follicular thyroid carcinoma |
UK Market Information
Propylthiouracil currently holds no marketing authorisation in the UK evidence pack (market status: Not marketed; 0 licences on record). No product-level dosage form or indication data is available for review.
Safety Considerations
Please refer to the SmPC and BNF for safety information. Report suspected adverse reactions via the Yellow Card Scheme.
Note: TFDA/regulatory warnings and contraindications data for this drug are currently missing (a blocking data gap), which prevents a full safety pre-assessment for this candidate.
Conclusion and Next Steps
Decision: Hold
Rationale: Evidence for this specific indication is limited to case reports and preclinical/mechanistic studies (L4), with no clinical trials evaluating propylthiouracil in TRβ-mutation-related thyroid hormone resistance. The drug has no current UK marketing authorisation, and a blocking data gap in regulatory safety information (warnings/contraindications) prevents progression to safety pre-assessment (S1).
To proceed, the following is needed:
- TFDA/MHRA SmPC warnings and contraindications (resolve blocking data gap DG001)
- Confirmed mechanism of action data from DrugBank (resolve DG002)
- Prospective clinical evidence (case series or trial) specifically evaluating propylthiouracil in TRβ-mutation RTH, rather than incidental misdiagnosis reports
- Confirmation of UK marketing/importation pathway, given current “Not marketed” status
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.