Pathways

Metabolites of Terazosin are predicted with biotransformer.

Terbinafine (commonly known as Lamisil or Silka cream) is a synthetic allylamine anti-fungal used mainly for athletes foot and other fungal skin infections. While Terbinafine is most commonly used against the fungus species Trichophyton rubrum and Trichophyton mentagrophytes, but the ergosterol biosynthesis pathway for these species has not been studies enough to know the enzymes used for sure. Candida albicans is a fungus that Terbinafine can be used against and the enzyme squalene monooxygenase, which is the enzyme inhibited by this drug, has been properly researched for Candida albicans where it hasn't for other fungus species. Terbinafine can also be used against other Trichophyton species; Microsporum canis; Epidermophyton floccosum,11; Tinea species; Candida albicans and Malassezia furfur if infections of the skin. Terbinafine works by inhibiting squalene monooxygenase which is an essential enzyme of Ergosterol biosynthesis. Terbinafine is transported into the fungal cell vis diffusion. Squalene monooxygenase catalyzes the synthesis of (S)-2,3-epoxysqualene from squalene. Since it is inhibited, it cannot continue on to synthesize lanosterol which is essential in the synthesis of ergosterol. Without ergosterol in the cell membrane, the cell membrane sees increased permeability which allows intracellular components to leak out of the cell. Ergosterol is also essential in cell membrane integrity so without that, eventually the cell collapses and dies.. The fungal cell also cannot synthesize new cell membranes for new fungus cells if there is no ergosterol. The inhibition of squalene monooxygenase also causes a buildup of squalene which is toxic to the fungal cell.

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.

Terbutaline is a beta-2 adrenergic receptor agonist that is used primarily as a bronchodilator. It can be found under the brand name Bricanyl and is an inhaled drug with a short duration. It is used for the prevention and reversal of bronchospasm and for treatment of asthma and bronchitis. Terbutaline relaxes the smooth muscles in the bronchioles by binding to the beta-2 adrenergic receptor and starting a G protein signalling cascade that activates adenylyl cyclase. Once terbutaline is administered and it binds to the beta-2 adrenergic receptor, the G protein signalling cascade begins. The alpha and beta/gamma subunits of the G protein separate and GDP is replaced with GTP on the alpha subunit. This alpha subunit then activates adenylyl cyclase which converts ATP to cAMP. cAMP then activates protein kinase A (PKA) which in turn phosphorylates targets and inhibits MLCK through decreased calcium levels causing muscle relaxation. PKA can phosphorylate certain Gq-coupled receptors as well as phospholipase C (PLC) and thereby inhibit G protein-coupled receptor (GPCR) -PLC-mediated phosphoinositide (PI) generation, and thus calcium flux. PKA phosphorylates the inositol 1,4,5-trisphosphate (IP3) receptor to reduce its affinity for IP3 and further limit calcium mobilization. PKA phosphorylates myosin light chain kinase (MLCK) and decreases its affinity to calcium calmodulin, thus reducing activity and myosin light chain (MLC) phosphorylation. Inhibits the phosphorylation of myosin. PKA also phosphorylates KCa++ channels in ASM, increasing their open-state probability (and therefore K+ efflux) and promoting hyperpolarization. Since myosine light chain kinase is not activated, Serine/threonine-protein phosphatase continues to dephosphorylate myosin LC-P, and more cannot be synthesized so myosin remains unbound from actin causing muscle relaxation. This relaxation of the smooth muscles in the lungs causes the bronchial airways to relax which causes bronchodialation, making it easier to breathe. Some side effects from use of terbutaline may include nervousness, drowsiness, weakness, nausea, and headache. Terbutaline may be administered via respiratory inhalation, oral tablets, or subcutaneous injections.

Metabolites of Terbutaline are predicted with biotransformer.

Terconazole is an triazole anti-fungal drug that is mainly used to treat vaginal yeast infections (vaginal candidiasis). The drug comes in a cream or suppository form with high levels of safety, efficacy, and tolerability for both. Terconazole is applied topically to the vagina where it is absorbed into the infected cells, and then diffuses into the candida cell. Terconazole inhibits lanosterol 14-alpha demethylase in the endoplasmic reticulum of fungal cells. Lanosterol 14-alpha demethylase is the enzyme that catalyzes the synthesis of 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol from lanosterol. With this enzyme inhibited ergosterol synthesis cannot occur which causes a significant low concentration of ergosterol in the fungal cell. Ergosterol is essential in maintaining membrane integrity in fungi. Without ergosterol, the fungus cell cannot synthesize membranes thereby increasing fluidity and preventing growth of new cells. This leads to cell lysis which causes it to collapse and die.