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Mechanism of action of Amorolfine

Mar 31，2022

Amorolfine is a phenyl-propyl-morpholine antifungal derivative which was introduced to the market in 1981. Its chemical name is cis-4-[(RS)-3-[4-(1,1-dimethylpropyl) phenyl]-2-methylpropyl]-2,6- dimethyl morpholine hydrochloride (C21H35NO.HCl) and its molecular weight is 353.97. The chemical structure of amorolfine hydrochloride is shown below.

Amorolfine is available for topical use in 0.25% cream and 5% nail lacquer formulation for the treatment of onychomycosis in European countries and Japan. However, amorolfine is not approved in the USA for such indications. The major advantage of this new antimycotic drug presumably lies in its potential for use as 5% nail lacquer in the treatment of onychomycosis caused by dermatophytes and Candida spp.

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Mechanism of action

The fungistatic or fungicidal activity of amorolfine depends primarily on its ability to inhibit the formation of ergosterol, a component of the fungal cell membrane. Amorolfine interferes with ergosterol synthesis at two stages, the 14-reduction and the 7–8 isomerization steps.

As a consequence, 24-methylene ignosterol is accumulated in the cell membrane and ergosterol is depleted. These effects are both time and concentration dependent. At a molecular level, amorolfine does not affect cellular respiration or synthesis of DNA, RNA, protein, or carbohydrate at the inhibitory drug concentration. It is thought that the antifungal activity of amorolfine is mainly due to inhibition of D14 reductase. Amorolfine has also been reported to cause selective intracellular accumulation of squalene in Trichophyton organisms, but not in C. albicans. A differential inhibitory effect on the squalene epoxidase from T. rubrum and C. albicans has been described.

Dosage

Amorolfine is available in topical formulations of 0.25% amorolfine cream and 5% nail lacquer. For superficial dermatomycosis, it is recommended that the 0.25% cream be applied to affected areas once daily for 2–4 weeks. For the treatment of onychomycosis, 5% nail lacquer should be applied to affected nails once weekly – then weekly applications continued until the nail is regenerated and the affected areas cured. Fingernails generally require treatment for six months and toenails require 12 months' treatment.

Bioavailability

Less than 0.5 ng equivalents per milliliter (detection limit) of intact drug was detected in plasma samples from normal volunteers following a single dose of 0.5 g of 0.25% radiolabeled amorolfine cream to intact or stripped skin. Amorolfine was not detected in the plasma of 19 patients randomized to receive amorolfine 5% nail lacquer either once or twice weekly. Despite potent in vitro activity against various fungi, testing in experimental animal models showed that amorolfine is inactive when administered orally for the treatment of life-threatening mycoses.

This lack of systemic activity has been postulated to result from rapid metabolism or extensive protein binding. As a result, the therapeutic efficacy of amorolfine is limited to superficial fungal infections, such as onychomycosis, dermatomycosis, and vulvovaginal candidiasis.

Side effects

Topical application of amorolfine (5% nail lacquer and 0.25% cream) is generally well tolerated, with up to 5% of patients reporting minor symptoms. In patients using the nail lacquer, these events included burning, itching, redness, and local pain, which were toleratable and confined to the application site. Adverse effects of scaling, weeping, blistering, and edema have also been described for the cream formulation.

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