Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria
Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown t...
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| Format: | Article |
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MDPI AG
2021-05-01
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| Series: | Journal of Personalized Medicine |
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| Online Access: | https://www.mdpi.com/2075-4426/11/6/485 |
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| author | Ganeko Bernardo-Seisdedos Jorge M. Charco Itxaso SanJuan Sandra García-Martínez Pedro Urquiza Hasier Eraña Joaquín Castilla Oscar Millet |
| author_facet | Ganeko Bernardo-Seisdedos Jorge M. Charco Itxaso SanJuan Sandra García-Martínez Pedro Urquiza Hasier Eraña Joaquín Castilla Oscar Millet |
| author_sort | Ganeko Bernardo-Seisdedos |
| collection | DOAJ |
| description | Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that it also acts as a pharmacological chaperone in CEP, presenting a specific activity in deleterious mutations in UROIIIS. Despite CPX is active at subtoxic concentrations, acute gastrointestinal (GI) toxicity was found due to the precipitation in the stomach of the active compound and subsequent accumulation in the intestine. To increase its systemic availability, we carried out pharmacokinetic (PK) and pharmacodynamic (PD) studies using alternative formulations for CPX. Such strategy effectively suppressed GI toxicity in WT mice and in a mouse model of the CEP disease (<i>UROIIIS</i><sup>P248Q/P248Q</sup>). In terms of activity, phosphorylation of CPX yielded good results in CEP cellular models but showed limited activity when administered to the CEP mouse model. These results highlight the need of a proper formulation for pharmacological chaperones used in the treatment of rare diseases. |
| first_indexed | 2024-03-10T10:57:53Z |
| format | Article |
| id | doaj.art-b8f89cc718004f04815e7bef592dd414 |
| institution | Directory Open Access Journal |
| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-10T10:57:53Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Personalized Medicine |
| spelling | doaj.art-b8f89cc718004f04815e7bef592dd4142023-11-21T21:47:36ZengMDPI AGJournal of Personalized Medicine2075-44262021-05-0111648510.3390/jpm11060485Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic PorphyriaGaneko Bernardo-Seisdedos0Jorge M. Charco1Itxaso SanJuan2Sandra García-Martínez3Pedro Urquiza4Hasier Eraña5Joaquín Castilla6Oscar Millet7ATLAS Molecular Pharma S. L. Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, SpainATLAS Molecular Pharma S. L. Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, SpainCIC bioGUNE, BRTA, Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, SpainATLAS Molecular Pharma S. L. Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, SpainCIC bioGUNE, BRTA, Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, SpainATLAS Molecular Pharma S. L. Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, SpainATLAS Molecular Pharma S. L. Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, SpainATLAS Molecular Pharma S. L. Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, SpainCongenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that it also acts as a pharmacological chaperone in CEP, presenting a specific activity in deleterious mutations in UROIIIS. Despite CPX is active at subtoxic concentrations, acute gastrointestinal (GI) toxicity was found due to the precipitation in the stomach of the active compound and subsequent accumulation in the intestine. To increase its systemic availability, we carried out pharmacokinetic (PK) and pharmacodynamic (PD) studies using alternative formulations for CPX. Such strategy effectively suppressed GI toxicity in WT mice and in a mouse model of the CEP disease (<i>UROIIIS</i><sup>P248Q/P248Q</sup>). In terms of activity, phosphorylation of CPX yielded good results in CEP cellular models but showed limited activity when administered to the CEP mouse model. These results highlight the need of a proper formulation for pharmacological chaperones used in the treatment of rare diseases.https://www.mdpi.com/2075-4426/11/6/485ciclopiroxpharmacological chaperonesporphyriadrug discoveryprotein stability |
| spellingShingle | Ganeko Bernardo-Seisdedos Jorge M. Charco Itxaso SanJuan Sandra García-Martínez Pedro Urquiza Hasier Eraña Joaquín Castilla Oscar Millet Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria Journal of Personalized Medicine ciclopirox pharmacological chaperones porphyria drug discovery protein stability |
| title | Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria |
| title_full | Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria |
| title_fullStr | Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria |
| title_full_unstemmed | Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria |
| title_short | Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria |
| title_sort | improving the pharmacological properties of ciclopirox for its use in congenital erythropoietic porphyria |
| topic | ciclopirox pharmacological chaperones porphyria drug discovery protein stability |
| url | https://www.mdpi.com/2075-4426/11/6/485 |
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