Bernardo-Seisdedos Ganeko, Charco Jorge M, SanJuan Itxaso, García-Martínez Sandra, Urquiza Pedro, Eraña Hasier, Castilla Joaquín, Millet Oscar
ATLAS Molecular Pharma S. L. Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, Spain.
CIC bioGUNE, BRTA, Parque Tecnológico de Vizcaya, Ed. 800, 48160 Derio, Spain.
J Pers Med. 2021 May 28;11(6):485. doi: 10.3390/jpm11060485.
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 (). 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.
先天性红细胞生成性卟啉病（CEP），也称为冈瑟病，是由于血红素途径中第四种酶尿卟啉原III合酶（UROIIIS）活性不足所致。环吡酮（CPX）是一种未按药品说明书用药的药物，通常作为抗真菌药局部使用。最近研究表明，它在CEP中还可作为一种药理伴侣，对UROIIIS中的有害突变具有特定活性。尽管CPX在亚毒性浓度下具有活性，但由于活性化合物在胃中沉淀并随后在肠道中蓄积，仍发现有急性胃肠道（GI）毒性。为提高其全身可用性，我们使用CPX的替代制剂进行了药代动力学（PK）和药效学（PD）研究。该策略有效抑制了野生型小鼠和CEP疾病小鼠模型中的胃肠道毒性（）。在活性方面，CPX磷酸化在CEP细胞模型中产生了良好效果，但在给予CEP小鼠模型时活性有限。这些结果凸显了对用于治疗罕见病的药理伴侣进行适当制剂的必要性。
