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Pathway Description
Terbinafine Metabolism
Homo sapiens
Metabolic Pathway
Terbinafine can be taken orally as a pill. This pill is digested then transported from the intestine into the intestinal epithelial cell possibly via solute carrier family 15 member 1, one of 3 drug transporters into epithelial cells. It is then transported into blood vessels via ATP-binding cassette sub-family C member 3. Once in the blood it travels to the liver where it inhibits squalene monoxygenase, despite having a higher affinity for fungal squalene monoxygenase. In homo sapiens squalene monooxygenase is essential in the biosynthesis of Cholesterol. Like in fungal cells it catalyzes the synthesis of (S)-2,3-epoxysqualene from squalene. (S)-2,3-Epoxysqualene is then catalyzed by lanosterol synthase into lanosterol which then continues into cholesterol biosynthesis. Cholesterol, like ergosterol is essential in membrane integrity by synthesizing fatty acids. It also produces steroid hormones, bile acids, and vitamin D. A lack of cholesterol can cause cholesterol jaundice. The inhibition of squalene monooxygenese causes a increased concentration of squalene which in high concentrations is toxic to the liver. This can cause liver damage or liver death.
Terbinafine also inhibits Cytochrome P450 2D6 which is an enzyme present in pregnancy. It is used in the metabolism of fatty acids, steroids and retinoids. For this reason Terbinafine isn't recommended for pregnant people.
Terbinafine is metabolized into many different metabolites. Terbinafine is metabolized by CYP450 1A2, 2B6, 2C8, 2C9, and 2C19 to make hydroxyterbinafine which is metabolized into N-Desmethylhydroxyterbinafine by CYP450 3A4, 2B6, 1A2, 2C9, 2C8, and 2C19; and it is metabolized into Carboxyterbinafine by CYP450 1A2, 2B6, 2C8, 2C9, and 2C19. Terbinafine is then also metabolized into N-Desmethylterbinafine by CYP450 2C9, 2C8, 1A2, 2B6, 2C19, and 3A4 which is dihydroxylated into 2 different dihydrodial derivatives as well as being metabolized into N-Desmethylhydroxyterbinafine by CYP450 1A2, 2B6, 2C8, 2C9, and 2C19. Terbinafine is also metabolized into 1-Naphthaldehyde with the same enzymes as N-Desmethylterbinafine. This is predicted by biotransformer to be metabolized into 1-Nahthalenemethanol by CYP450 3A4 and 1-Naphthoic acid by CYP450 1A2. Finally Terbinafine can be dihydroxylated to two different dihydrodiols which are N-demethylated into desmethyldihydrodiol.
These metabolites are transported back into the blood where they travel to the kidneys and are excreted through the urine. 80% is excreted in the urine. The remaining 20% of metabolites are transported from the liver into the bile ducts which travels through the ducts into the intestine where they are excreted through the feces. Terbinafine is not present in the urine.
References
Terbinafine Metabolism References
Meletiadis J, Chanock S, Walsh TJ: Human pharmacogenomic variations and their implications for antifungal efficacy. Clin Microbiol Rev. 2006 Oct;19(4):763-87. doi: 10.1128/CMR.00059-05.
Vickers AE, Sinclair JR, Zollinger M, Heitz F, Glanzel U, Johanson L, Fischer V: Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug Metab Dispos. 1999 Sep;27(9):1029-38.
Jensen JC: Clinical pharmacokinetics of terbinafine (Lamisil). Clin Exp Dermatol. 1989 Mar;14(2):110-3. doi: 10.1111/j.1365-2230.1989.tb00904.x.
Sander CS, Hipler UC, Wollina U, Elsner P: Inhibitory effect of terbinafine on reactive oxygen species (ROS) generation by Candida albicans. Mycoses. 2002 Jun;45(5-6):152-5.
Darkes MJ, Scott LJ, Goa KL: Terbinafine: a review of its use in onychomycosis in adults. Am J Clin Dermatol. 2003;4(1):39-65
Ryder NS: Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol. 1992 Feb;126 Suppl 39:2-7. [
Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1.
Vickers AE, Sinclair JR, Zollinger M, Heitz F, Glanzel U, Johanson L, Fischer V: Multiple cytochrome P-450s involved in the metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug Metab Dispos. 1999 Sep;27(9):1029-38.
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
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