Pharmacokinetics of Ciclopirox Olamine after Buccal Administration in Rabbits

Lukášová, Ivana; Muselík, Jan; Vetchý, David; Gajdziok, Jan; Gajdošová, Markéta; Juřica, Jan; Knotek, Z.; Hauptman, Karel; Jekl, Vladimír

doi:10.2174/1567201813666160502142856

Cited by 5 publications

(2 citation statements)

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“…Pharmacokinetic experiments have previously shown that CPX's half-life in the organism is short, with strong affinity for serum albumin and fast catabolism mediated by a glucuronidation reaction (37,38). We found that glucuronidation occurred at the hydroxyl moiety and that CPXglu was incapable of reducing porphyrins in the CEP cellular models (Fig.…”

Section: Preliminary Pharmacokinetics and Dose-response Studiesmentioning

confidence: 69%

“…2G). To quantify the effective concentration of CPX administered within the pellets, we have developed an NMR-based method for the analysis of the active and glucuronide forms of CPX in serum and urine (see Materials and Methods) and cross-validated it against the most conventional HPLC-based method (38). The average concentration of active CPX in serum was CPX = 2.79 ± 0.6 mM and CPXglu = 12 ± 1.2 mM, which is equivalent to an intake (gavage) of 300 mg/m 2 and close to the toxicity limit for the drug (39).…”

Section: Preliminary Pharmacokinetics and Dose-response Studiesmentioning

confidence: 99%

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Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria

et al. 2018

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Congenital erythropoietic porphyria is a rare autosomal recessive disease produced by deficient activity of uroporphyrinogen III synthase, the fourth enzyme in the heme biosynthetic pathway. The disease affects many organs, can be life-threatening, and currently lacks curative treatments. Inherited mutations most commonly reduce the enzyme's stability, altering its homeostasis and ultimately blunting intracellular heme production. This results in uroporphyrin by-product accumulation in the body, aggravating associated pathological symptoms such as skin photosensitivity and disfiguring phototoxic cutaneous lesions. We demonstrated that the synthetic marketed antifungal ciclopirox binds to the enzyme, stabilizing it. Ciclopirox targeted the enzyme at an allosteric site distant from the active center and did not affect the enzyme's catalytic role. The drug restored enzymatic activity in vitro and ex vivo and was able to alleviate most clinical symptoms of congenital erythropoietic porphyria in a genetic mouse model of the disease at subtoxic concentrations. Our findings establish a possible line of therapeutic intervention against congenital erythropoietic porphyria, which is potentially applicable to most of deleterious missense mutations causing this devastating disease.

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Section: Preliminary Pharmacokinetics and Dose-response Studiesmentioning

confidence: 69%

Section: Preliminary Pharmacokinetics and Dose-response Studiesmentioning

confidence: 99%