Clotrimazole is an anti-fungal drug that is typically applied topically in the form of a cream. It can also be taken as a troche formulation (a tablet that dissolves on your tongue) for throat infections. It has also become a drug of interest in treating sickle cell disease, malaria, and some cancers. More research is needed for that. Clortrimazole is used for fungal infections caused by Candida albicans or Malassezia furfur. Once Clotrimazole is applied to the infected area, such as the skin, it enters the infected cells by way of the transporter P-glycoprotein. Once in the infected cell it targets Lanosterol 14-alpha demethylase, a cytochrome enzyme, and inhibits it. Lanosterol 14-alpha demethylase catalyzes Lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol which is used in ergosterol biosynthesis. Ergosterol is essential for cell membrane stability and synthesis. Clotrimazole also inhibits Ergosterol itself by binding to it in the cell membrane, creating a transmembrane channel that increases cell permiability allowing leakage of cellular components. Eventually this compromises cell integrity and causes cell death. The fungal cell also cannot synthesize new bud membranes to make new cells. Clotrimazole also inhibits Intermediate conductance calcium-activated potassium channel protein 4 which is present in non-excitable cells of homo sapiens. This channel releases potassium from the cell when calcium enters in order to keep non-excitable cells polarized. The blocking of this channel means that when calcium enters the cell, potassium cannot leave the cell and hypopolarization or depolarization occurs in the cell. This depolarization would have many unknown effects on the cell as many compounds and enzymes in the cell require certain polarization to function properly. Clotrimazole is a partial agonist to Hydroxycarboxylic acid receptor 2 on adipose cells or possibly the spleen if it were to reach the spleen. Hydroxycarboxylic acid receptor 2 is a receptor that releases adiponectin. Adiponectin is a fat-derived hormone that causes insulin resistance in the liver and skeletal muscles, therefore Clotrimazole causes a partial inhibition of the insulin pathway. Hydroxycarboxylic acid receptor 2 also inhibits the enzyme anenylyl cyclase which is the enzyme that makes cAMP from ATP. cAMP is essential for lypolysis which is the synthesis of glycerol and 3-fatty acids. The Hydroxycarboxylic acid receptor has a high affinity for (D)-beta-hydroxybutyrate and nicotinic acid, but only in high enough doses that are not present in the human body. Therefore this receptor can only be activated by drugs such as Clotrimazole.

Clotrimazole Pathway References