Terbinafine targets squalene monooxygenase (squalene epoxidase), a key enzyme in the ergosterol biosynthesis pathway. It acts as a potent non-competitive inhibitor of this enzyme. By blocking squalene epoxidase, the compound prevents the conversion of squalene to 2,3-oxidosqualene, thereby depleting ergosterol, an essential component of fungal cell membranes. The compound shows selectivity for fungal over mammalian squalene epoxidase.

In vitro, terbinafine predominantly acts as a fungicidal agent against a variety of fungal diseases, such as filamentous, dimorphic, and dermatophytes. At the squalene epoxidation site, terbinafine selectively inhibits the formation of fungal ergosterol. The intermediate squalene is quickly accumulated by treated fungal cells [1].
In vitro, terbinafine demonstrates potent antifungal activity against a broad range of dermatophytes and yeasts. Its activity is assessed by determining minimum inhibitory concentrations (MIC) using broth microdilution methods. The compound shows potent activity against Trichophyton species, Microsporum species, and Epidermophyton floccosum. It also exhibits activity against certain Candida species.

Terbinafine has been shown to be particularly effective against experimental dermatophytosis both when applied topically and when taken orally. Skin temperature in guinea pigs afflicted with fungus decreased significantly during the fourth terbinafine therapy [2].
In vivo, terbinafine is effective against various fungal infections. It is used topically and orally for the treatment of dermatophyte infections of the skin and nails. The drug is also effective against pityriasis versicolor. Oral administration achieves therapeutic concentrations in the stratum corneum, hair, and nails due to its lipophilic nature and high tissue affinity.

In vitro enzyme assays for terbinafine measure its inhibition of squalene epoxidase activity. The enzyme is incubated with radiolabeled squalene substrate and varying concentrations of the compound. The reaction product, 2,3-oxidosqualene, is quantified by chromatographic methods. The Ki value is determined from enzyme kinetic studies using fungal microsomal preparations.

In vitro cell-based assays for terbinafine use fungal cell cultures, typically Candida species or dermatophytes. Cells are cultured in appropriate growth media and exposed to serial dilutions of the compound. Antifungal activity is assessed by determining the minimum inhibitory concentration (MIC) using broth microdilution methods per CLSI guidelines. Cell proliferation is measured by optical density or colony counting after 24-48 hours of incubation.

In vivo animal models for terbinafine include guinea pig models of dermatophytosis. Animals are infected with Trichophyton mentagrophytes on shaved skin, then treated with topical or oral terbinafine at various doses. Efficacy is evaluated by clinical scoring of skin lesions and mycological culture of skin samples. Pharmacodynamic parameters such as the effective dose for 50% cure (ED50) are calculated.

Absorption, Distribution and Excretion
Oral terbinafine has an absorption rate exceeding 70%, but its bioavailability after first-pass metabolism is only 40%. The peak plasma concentration (Cmax) is 1 µg/mL, the time to peak concentration (Tmax) is 2 hours, and the area under the curve (AUC) is 4.56 µgh/mL. With 1% topical terbinafine, the Cmax increases from 949-1049 ng/cm², and the AUC increases from 9694-13492 ng/cm²/h within one week. Approximately 80% of terbinafine is excreted in the urine, with the remainder excreted in the feces. Unmetabolized parent drug is not present in the urine. The steady-state volume of distribution for a single oral dose of 250 mg terbinafine is 947.5 L or 16.6 L/kg. The clearance of a single oral dose of 250 mg terbinafine is 76 L/h or 1.11 L/h/kg.

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Metabolism/Metabolites
Terbinafine can be deaminated via CYP2C9, 2B6, 2C8, 1A2, 3A4, and 2C19 to generate 1-naphthaldehyde. 1-Naphthaldehyde is then oxidized to 1-naphthoic acid or reduced to 1-naphthylethanol. Terbinafine can also be hydroxylated by CYP1A2, 2C9, 2C8, 2B6, and 2C19 to hydroxyterbinafine. Hydroxyterbinafine is then oxidized by CYP3A4, 2B6, 1A2, 2C9, 2C8, and 2C19 to carboxyterbinafine or N-demethylated to demethylhydroxyterbinafine. Terbinafine can also be N-demethylated to demethylterbinafine. Demethylterbinafine is then dihydroxylated to demethyldihydrodiol or hydroxylated to demethylhydroxyterbinafine. Finally, terbinafine is dihydroxylated to form dihydrodiol, which is then N-demethylated to form demethyldihydrodiol. Known metabolites of terbinafine include hydroxyterbinafine, N-demethylterbinafine, and 1-naphthaldehyde. The effective half-life of orally administered terbinafine is approximately 36 hours. However, due to its distribution to the skin and adipose tissue, its terminal half-life is 200-400 hours. The half-life of 1% topical terbinafine increases from approximately 10-40 hours within the first seven days.
Terbinafine free base has a molecular formula of C21H25N and a molecular weight of 291.43. It is highly lipophilic with excellent oral bioavailability. Following oral administration, it is extensively distributed into tissues, primarily skin, hair, and nails. The drug is metabolized in the liver by cytochrome P450 enzymes to inactive metabolites. The terminal elimination half-life is approximately 200-400 hours after multiple dosing due to slow release from tissues.

Hepatotoxicity
Terbinafine-induced drug-induced liver injury was discovered shortly after its clinical introduction. Less than 1% of patients treated with oral terbinafine develop elevated serum transaminases, which are usually asymptomatic and resolve spontaneously without discontinuation of the drug. It is estimated that the probability of developing elevated serum transaminases requiring discontinuation after 2 to 6 weeks of treatment is approximately 0.31%, and after more than 8 weeks of treatment, it is approximately 0.44%. Clinically significant terbinafine-induced liver injury is rare (approximately 1 case per 50,000 to 120,000 prescriptions), but numerous case reports and even case series have been documented in the literature. Liver injury typically occurs within the first 6 weeks of treatment. The injury pattern may initially be hepatocellular or cholestatic, but it usually progresses to cholestatic and may last longer (Case 1 and 2). Some cases may progress to disappearance of bile duct syndrome. Hypersensitivity reactions (rash, fever, eosinophilia) are uncommon, and even when they occur, they are usually mild to moderate. Autoantibody formation is rare. In addition, cases of severe hepatocellular injury with acute liver failure have been reported. These cases are characterized by rapid onset, significantly elevated serum transaminase levels, and progressive jaundice and liver failure. Terbinafine has also been associated with cases of Stevens-Johnson syndrome, in which liver damage may be masked by rash and allergic symptoms. Probability Score: B (Very likely to cause clinically apparent liver damage). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Limited information suggests that a low concentration of terbinafine in breast milk from daily oral administration by the mother is not expected to have any adverse effects on breastfed infants, especially those older than 2 months. Infants should be monitored for jaundice or other signs of hepatotoxicity, especially younger exclusively breastfed infants. Some data recommend avoiding oral terbinafine during lactation. Topical terbinafine during lactation has not been studied. Because the absorption rate after topical application is only about 1%, the risk to breastfed infants is considered low. Avoid applying to the nipple area and ensure that the infant's skin does not come into direct contact with the treated skin area. Only water-soluble creams, gels, or liquid products should be applied to the breast, as ointments may expose the infant to high concentrations of mineral oil through licking.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Terbinafine binds to >99% of proteins in plasma, primarily serum albumin, high-density lipoprotein, and low-density lipoprotein, with lower binding to α-1-acid glycoprotein.
The toxicity profile of terbinafine includes gastrointestinal disturbances, headache, and skin reactions as common adverse effects. Hepatotoxicity is a rare but serious adverse event, requiring liver function monitoring during prolonged therapy. Taste disturbances, including loss of taste, have also been reported. At therapeutic doses, the drug is generally well-tolerated, but caution is advised in patients with pre-existing liver disease.

[1]. Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol. 1992 Feb;126 Suppl 39:2-7.

[2]. Preclinical evaluation of terbinafine in vivo. Clin Exp Dermatol. 1989 Mar;14(2):104-7.

[3]. Mupirocin vs terbinafine in impetigo.Indian J Pediatr. 2002 Aug;69(8):679-82.

Terbinafine is a tertiary amine, chemically named N-methyl-1-naphthylmethylamine, in which the amino hydrogen is replaced by a 3-(tert-butylethynyl)allyl group. It is an oral antifungal drug (usually administered as a hydrochloride salt) used to treat skin and nail infections. It is an EC 1.14.13.132 (squalene monooxygenase) inhibitor, a P450 inhibitor, and a sterol biosynthesis inhibitor. It is a tertiary amine, alkyne, naphthalene, enyne, and allylamine antifungal drug. It is the conjugate base of terbinafine (1+). Terbinafine hydrochloride (Lamisil) is a synthetic allylamine antifungal drug. It is highly lipophilic and readily accumulates in the skin, nails, and adipose tissue. Like other allylamine drugs, terbinafine inhibits ergosterol synthesis by inhibiting fungal squalene monooxygenase (also known as squalene epoxidase). Squalene monooxygenase is an enzyme in the fungal cell wall synthesis pathway. Terbinafine hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on December 30, 1992. Terbinafine is an allylamine antifungal drug. Terbinafine is an orally and topically effective allylamine fungicide used to treat superficial fungal infections of the skin and nails. Terbinafine has a clear association with rare cases of acute liver injury, which can be severe and sometimes fatal. Terbinafine is a synthetic allylamine derivative with antifungal activity. Terbinafine works by inhibiting squalene epoxidase, thereby blocking the biosynthesis of ergosterol (an important component of the fungal cell membrane). Therefore, the drug disrupts the synthesis of the fungal cell membrane and inhibits fungal growth. A naphthalene derivative that inhibits fungal squalene epoxidase is used to treat dermatophyte infections of the skin and nails. See also: Terbinafine Hydrochloride (active ingredient); Betamethasone Acetate; Florfenicol; Terbinafine (ingredient); Florfenicol; Mometasone Furoate; Terbinafine (ingredient)... See more...

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Drug Indications
Terbinafine hydrochloride is indicated for the treatment of fungal infections of the skin and nails caused by Trichophyton spp., Microsporum canis, Epidermophyton floccosum, and Trichophyton spp. Terbinafine hydrochloride may also be used to treat yeast infections of the skin caused by Candida spp. and Malassezia furfur.
FDA Label

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Mechanism of Action
Terbinafine inhibits squalene monooxygenase (also known as squalene epoxidase), preventing the conversion of squalene to 2,3-oxosqualene, a step in the synthesis of ergosterol. This inhibition leads to a reduction in ergosterol that is normally incorporated into the cell wall, resulting in squalene accumulation. The formation of numerous squalene-containing vesicles in the cytoplasm may cause other lipids to leak from the cell wall, further weakening the cell wall.

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Pharmacodynamics
Terbinafine is an allylamine antifungal drug that inhibits squalene epoxidase (also known as squalene monooxygenase) to prevent ergosterol formation, leading to squalene accumulation and thus weakening the fungal cell wall. Terbinafine is widely distributed in tissues and has a long terminal elimination half-life, resulting in a long duration of action. Overdose of terbinafine is rare even at therapeutic doses, thus its therapeutic index is broad. Patients taking oral terbinafine should undergo liver function tests before treatment to reduce the risk of liver damage.
Terbinafine free base is the non-salt form of terbinafine, a synthetic allylamine antifungal agent. It is used for the treatment of dermatophyte infections including onychomycosis, ringworm, and athlete's foot. The compound acts by inhibiting squalene epoxidase, depleting ergosterol in fungal cell membranes. Terbinafine is available in oral and topical formulations. It is used for research purposes.

C21H25N

291.4299

291.198

91161-71-6

Terbinafine hydrochloride;78628-80-5;Terbinafine-d3 hydrochloride;1310012-15-7;Terbinafine-d7;1185240-27-0;Terbinafine lactate;335276-86-3

1549008

White to yellow solid powder

1.0±0.1 g/cm3

417.9±33.0 °C at 760 mmHg

183.7±22.3 °C

0.0±1.0 mmHg at 25°C

1.586

6.61

0

1

5

22

428

0

CC(C)(C)C#C/C=C/CN(C)CC1=CC=CC2=CC=CC=C21

DOMXUEMWDBAQBQ-WEVVVXLNSA-N

InChI=1S/C21H25N/c1-21(2,3)15-8-5-9-16-22(4)17-19-13-10-12-18-11-6-7-14-20(18)19/h5-7,9-14H,16-17H2,1-4H3/b9-5+

(E)-N,6,6-trimethyl-N-(naphthalen-1-ylmethyl)hept-2-en-4-yn-1-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~343.14 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (8.58 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 2.5 mg/mL (8.58 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 16.25 mg/mL (55.76 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)