Pathways

Tolmetin is an NSAID used to treat acute flares of various painful conditions and used for the long-term management of osteoarthritis, rheumatoid arthritis, and juvenile arthritis. Tolmetin possess anti-inflammatory, analgesic and antipyretic activity. It targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 converts arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Tolmetin inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fever is triggered by inflammatory and infectious diseases. Cytokines are produced in the central nervous system (CNS) during an inflammatory response. These cytokines induce COX-2 production that increases the synthesis of prostaglandin, specifically prostaglandin E2 which adjusts hypothalamic temperature control by increasing heat production. Because tolmetin decreases PGE2 in the CNS, it has an antipyretic effect. Antipyretic effects results in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

Metabolites of Tolmetin are predicted with biotransformer.

Tolnaftate is an over-the-counter anti-fungal agent mainly used to treat jock itch, athlete's foot and ringworm. It can come as a cream, powder, spray, or liquid aerosol. Tolnaftate is diffuses into the fungal cell. The exact mechanism of action for tolnaftate is unknown, however, it is believed to prevent the synthesis of ergosterol through inhibition of squalene epoxidase. 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.

Metabolites of Tolnaftate are predicted with biotransformer.

Tolpropamine is an alkylamine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.

Tolterodine is a muscarinic receptor antagonist used to treat overactive bladder with urinary incontinence, urgency, and frequency. It can be found under the brand names Detrol and Detrusitol. Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels. Tolterodine has a pronounced effect on bladder function. The main effects of tolterodine are an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure, consistent with an antimuscarinic action on the lower urinary tract. Tolterodine is an antimuscarinic medication that selectively and competitively binds to muscarinic M3 receptors in the bladder, thereby decreasing bladder contraction by decreasing detrusor muscle tone and increasing internal urethral sphincter tone. Possible side effects of using tolterodine may include dry mouth, headache, vertigo, and vomiting. Tolterodine can be administered as an oral capsule or tablet.

Toluene degradation allows bacteria to use toluene, a common environmental pollutant, as both a carbon and energy source. Toluene enters the bacterial cell by passive diffusion due to its hydrophobic nature. Once within the cell, toluene undergoes a variety of enzymatic reactions. The first step is for the Gamma-Subunit of benzylsuccinate synthase to convert it into benzylsuccinate. This intermediate is then converted to Benzylsuccinyl-CoA by subunit of Benzylsuccinate CoA-transferases. Subsequently, Benzylsuccinyl-CoA undergoes a series of enzymatic reactions to form Benzoylsuccinyl-CoA, and finally benzoyl-CoA, which enters the benzoate degradation pathway, providing the bacteria with energy and carbon for growth and survival.