Terbinafine

Absorption

Oral terbinafine is >70% absorbed but only 40% bioavailable after first pass metabolism, reaching a Cmax of 1μg/mL with a Tmax of 2 hours an an AUC of 4.56μg*h/mL. Over the course of a week, 1% topical terbinafine's Cmax increases from 949-1049ng/cm2 and the AUC increases from 9694-13,492ng/cm2/h.

Toxicity

The subcutaneous LD50 in rats and mice is >2g/kg. The TDLO for women is 210mg/kg/6W.
Overdose data with terbinafine is rare, however symptoms are expected to be nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache. Treat overdose with activated charcoal as well as symptomatic and supportive therapy.

Originator

Lamisil,Novartis,UK

The Uses of Terbinafine

Terbinafine (Lamisil) is a second-generation allylamine that is related to naftifine; however, it is 10 to 100 times more potent in vitro. It is fungicidal, whereas griseofulvin, ketoconazole, itraconazole, and other azole derivatives are all fungistatic. Because it is fungicidal, duration of therapy is shorter, and relapse rates are less than with other oral or topical therapies. Terbinafine acts by inhibiting squalene epoxidase and thereby decreasing synthesis of ergosterol, an essential component of fungal cell membranes. It is highly lipophilic and concentrates in the stratum corneum, sebum, and hair follicles. Slightly better cure rates are attained with b.i.d. than with daily dosing.

Background

Terbinafine hydrochloride (Lamisil) is a synthetic allylamine antifungal. It is highly lipophilic in nature and tends to accumulate in skin, nails, and fatty tissues. Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting the fungal squalene monooxygenase (also called squalene epoxidase), an enzyme that is part of the fungal cell wall synthesis pathway.
Terbinafine hydrochloride was granted FDA approval on 30 December 1992.

Indications

Terbinafine hydrochloride is indicated to treat fungal skin and nail infections caused by Trichophyton species, Microsporum canis, Epidermophyton floccosum, and Tinea species. Terbinafine hydrochloride also treats yeast infections of the skin caused by Candida species and Malassezia furfur.

Definition

ChEBI: A tertiary amine that is N-methyl-1-naphthalenemethylamine in which the amino hydrogen is replaced by a 3-(tertbutylethynyl)allyl group. An antifungal agent administered orally (generally as the hydrochloride salt) for the t eatment of skin and nail infections.

Indications

Terbinafine (Lamisil) is a second-generation allylamine that is related to naftifine; however, it is 10 to 100 times more potent in vitro. It is fungicidal, whereas griseofulvin, ketoconazole, itraconazole, and other azole derivatives are all fungistatic. Because it is fungicidal, duration of therapy is shorter, and relapse rates are less than with other oral or topical therapies.
Terbinafine acts by inhibiting squalene epoxidase and thereby decreasing synthesis of ergosterol, an essential component of fungal cell membranes. It is highly lipophilic and concentrates in the stratum corneum, sebum, and hair follicles. Slightly better cure rates are attained with b.i.d. than with daily dosing.

Manufacturing Process

To an ice-cooled solution of N-methyl-1-naphthalenemethylamine hydrochloride (2.1 g) in methanol (40 ml) and water (10 ml) was added sodium hydroxide powder (2 g) followed by dropwise addition of epichlorohydrin (8 ml). The mixture was heated at 60°C for 3 h, then cooled to room temperature. Volatile materials were removed in vacuo and the residue was taken up in ethyl acetate and washed with water. The organic phase was collected, dried over sodium sulfate, filtered and evaporated to dryness. The crude mixture was purified by flash chromatrography on silica gel (grade 9385, Merck, 230-400 mesh, 60 A) using a solvent gradient of a mixture of hexane and ethyl acetate (95:5, 90:10 and 85:15) as eluent, affording the N-methyl-N-naphthylmethyl-2,3-epoxypropane (1.85 g, 81.5%) as an oil.
To a solution of 3,3-dimethylbutyne (2.95 ml) in dry THF (50 ml) at -78°C was added a 2.5 M solution of n-BuLi in hexane (10 ml) dropwise. The mixture was allowed to warm to room temperature over 15 min and stirred at that temparature for a further 15 min, then was cooled back to -78°C and BF3OEt2 (3 ml) was added dropwise. The mixture was stirred for 15 min and 1.8 g of N-methyl-N-naphthylmethyl-2,3-epoxypropane, dissolved in THF (10 ml), was added dropwise. After stirring at -78°C for 2 h, saturated sodium bicarbonate solution (15 ml) was added, and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2 times 25 ml), and the combined organic fractions was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatrography on silica gel (grade 9385, Merck, 230-400 mesh, 60 a) using a mixture of hexane and ethyl acetate (85:15) as eluent, thereby affording the N-methyl-N-(1-naphthylmethyl)-2-hydroxy-heptan-4-ynyl-1-amine as an oil (1.95 g, 79%).
To an ice-cooled solution of N-methyl-N-(1-naphthylmethyl)-2-hydroxyheptan- 4-ynyl-1-amine (155 mg) in THF (10 ml) was added Et3N (0.35 ml) followed by methanesulfonyl chloride (0.075 ml). The resulting mixture was stirred at 0°C for 3 h, then filtered. The filtrate was concentrated in vacuo, dissolved in toluene (10 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.37 ml) was added. The resulting mixture was heated at 80°C for 4 h, cooled to room temperature then poured onto a silica gel column and eluted with hexane (100%) followed by a mixture of hexane and ethyl acetate (95:5). Thus, a mixture of E- and Z-isomers of N-methyl-N-(1- naphthylmethyl)-6,6-dimethylhept-2-en-4-ynyl)-1-amine were obtained in a ratio of 2:5 (95 mg, 66%).

Therapeutic Function

Antifungal

Synthesis Reference(s)

Tetrahedron Letters, 29, p. 1509, 1988 DOI: 10.1016/S0040-4039(00)80338-X

Antimicrobial activity

Terbinafine is active against a wide range of pathogenic fungi, including dermatophytes (Epidermophyton, Microsporum and Trichophyton spp.), various Candida spp., Aspergillus spp., some dimorphic fungi (Blastomyces dermatitidis, Histoplasma capsulatum and Sporothrix schenckii) and many dematiaceous fungi.

Acquired resistance

Resistance has not been reported.

Pharmaceutical Applications

A synthetic allylamine available as the hydrochloride for oral and topical administration.

Pharmacokinetics

Terbinafine is an allylamine antifungal that inhibits squalene epoxidase (also known as squalene monooxygenase) to prevent the formation of ergosterol and cause an accumulation of squalene, weakening the cell wall of fungal cells. Terbinafine distributes into tissues and has a long terminal elimination half life, so the duration of action is long. Overdose with terbinafine is rare, even above the therapeutic dose, so the therapeutic index is wide. Patients taking oral terbinafine should have liver function tests performed prior to treatment to reduce the risk of liver injury.

Pharmacokinetics

Oral absorption: 70–80%
C_max 250 mg oral: c. 1 mg/L after 2 h
Plasma half-life: c. 17 h
Volume of distribution: 1000 L
Plasma protein binding: >99%
Blood concentrations increase in proportion to dosage. It is lipophilic and is rapidly and extensively distributed to body tissues. It reaches the stratum corneum by diffusion through the dermis and epidermis, and secretion in sebum. Diffusion from the nail bed is the major factor in its rapid penetration of nails. It is metabolized by the liver and the inactive metabolites are mostly excreted in the urine. The elimination half-life is prolonged in patients with hepatic or renal impairment.

Clinical Use

Terbinafine hydrochloride can be used in Tinea pedis, tinea corporis, tinea cruris, tinea capitis, Onychomycosis caused by dermatophytes.

Side Effects

These include abdominal discomfort, loss of appetite, nausea, diarrhea, headache, impairment of taste, rash and urticaria. Serious skin reactions, including Stevens– Johnson syndrome, and rare hepatotoxic reactions, including jaundice, cholestasis and hepatitis, are occasionally encountered.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin.

Metabolism

Terbinafine can be deaminated to 1-naphthaldehyde by CYP2C9, 2B6, 2C8, 1A2, 3A4, and 2C19. 1-naphthaldehyde is then oxidized to 1-naphthoic acid or reduced to 1-naphthalenemethanol.
Terbinafine can also be hydroxylated by CYP1A2, 2C9, 2C8, 2B6, and 2C19 to hydroxyterbinafine. Hydroxyterbinafine is then oxidized to carboxyterbinafine or N-demethylated by CYP3A4, 2B6, 1A2, 2C9, 2C8, and 2C19 to desmethylhydroxyterbinafine.
Terbinafine can be N-demethylated to desmethylterbinafine. Desmethylterbinafine is then dihydroxylated to a desmethyldihydrodiol or hydroxylated to desmethylhydroxyterbinafine.
Finally, terbinafine can be dihydroxylated to a dihydrodiol which is then N-demethylated to a desmethyldihydrodiol.

Metabolism

Terbinafine undergoes extensive first pass loss. It is hepatically metabolised to two major inactive metabolites, 80% of which are renally excreted.