Pathways

Metabolites of Tolvaptan are predicted with biotransformer.

Topiramate is an anticonvulsant drug used in the control of epilepsy and in the prophylaxis and treatment of migraines. Topiramate is indicated for the following conditions: 1)Monotherapy for partial onset or primary generalized tonic-clonic seizures for patients 2 years of age and above 2)Adjunctive therapy for partial onset seizures or primary generalized tonic-clonic seizures for both adult and pediatric patients above 2 years old 3)Adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in patients above 2 years of age 4)Prophylaxis of migraine in children 12 years of age and older and adults. Topiramate is also used off-label as an adjunct therapy for weight management21 and for mood disorders. A seizure is an abnormal and unregulated electrical discharge occurring in the brain. This leads to transient interruption in brain function, manifested by reduced alertness, abnormal sensations, and focal involuntary movements or convulsions. Topiramate inhibits excitatory neurotransmitter activity by antagonizing AMPA and kainate glutamate receptors on the post synaptic membrane. These receptors are ligand gated ion channels, once bound to glutamate, the allow the influx of sodium ions into the post-synaptic neuron leading to depolarization and neuronal excitation. By antagonizing these glutamate receptors, topiramate prevents depolarization of the post-synaptic receptors. Topiramate may also prevent glutamate release from pre-synaptic neurons. This occurs by topiramate inhibiting voltage gated sodium channels in the presynaptic neuron, these sodium channels are responsible for allow sodium ion influx into the presynaptic neuron and depolarization. Depolarization leads to the opening of L-type voltage gated calcium channels at the neuronal terminal. This leads to the influx of calcium ions which stimulate the release of glutmate via exocytosis. By inhibiting the voltage gates sodium channels, depolarization in the presynaptic neurons is prevented, thus preventing calcium channel activation, calcium influx and glutamate release. Topiramate may also enhance the activity of GABA-A receptors on post synaptic neurons. GABA-A receptors, when activated, lead to the influx of negative chloride ions causing hyperpolarization and neuronal inhibition. Topiramate is a weak inhibitor of carbonic anhydrase; acidosis in the brain has partial protection against seizures by downregulating NMDA receptor activity. NMDA receptor are excitatory since they are ion channels that cause the influx of calcium ions into the neuron. By downregulating NMDA receptors, excitatory activity is reduced. Overall, topiramate functions are to reduce excitatory activity in neurons and enhance inhibitory activity. Most common adverse effects in epilepsy trials included the involvement of the central nervous system (paresthesia, fatigue, cognitive problems, dizziness, somnolence, psychomotor slowing, memory/concentration difficulties, nervousness, confusion), endocrine/metabolism (weight loss, anorexia), respiratory (infection), miscellaneous (fever, flushing).

Metabolites of Topiramate are predicted with biotransformer.

Topotecan, also known as Hycamtin, is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical cancer. It is a semi-synthetic derivative of camptothecin (obtained from the plant Camptotheca acuminata). This molecule is an anti-tumor drug with topoisomerase I-inhibitory activity. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and DNA repairs. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers. Topotecan is believed to exert its cytotoxic effects during the S-phase of the cell cycle replication. Topotecan binds to the topoisomerase I-DNA complex and prevents the religation of the single strand breaks and of any breaks in the DNA. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest. In consequence, this causes lethal double-stranded breaks in the DNA. The formation of this ternary complex eventually leads to apoptosis. Moreover, topotecan mimics a DNA base pair and binds at the site of DNA cleavage. Intercalation displaces the downstream DNA, thus preventing the religation of the cleaved strand.

Metabolites of Topotecan are predicted with biotransformer.

The TOR signalling pathway is responsible for the cellular reactions towards nutrient and energy availability and hypoxia/stress. When TOR1/2 is activated, it activates TAP42 which in turn can inhibit SIT4 . I can also activate TAP41 phosphorylation. The enzyme SIT4 activates the dephosphorylation of TIP41 which in turn inhibits TAP42. The enzyme SIT4 also activates the dephosphorylation of Ure2-Gln3 complex and the separation of Ure2 and Gln3. Gln3 then gets incorporated into the nucleus resulting in the transcription of GLN1, GLT1,GDH1,GDH2,GAP1,MEP2,DAL3,PUT1 which are incorporated into Nitrogen Utilization

Torasemide is a loop diuretic drug, administered orally or intravenously to treat hypertension and edema associated with heart failure, renal failure, or liver disease. It targets the nephrons of the kidney, mainly the ascending limb of the loop of henle. The basolateral membrane of the ascending loop of henle contains the Na+/K+ ATPase, Cl- channel and K+/Cl- co-transporter which are essential for the function for ion and water reabsorption. The Na+/K+ ATPase pumps Na+ from the cell into the peritubular fluid and K+ from the peritubular fluid into the cell. The K+/Cl- co-transporter moves K+ and Cl- from the cell into the peritubular fluid and the Cl- channel transports Cl- from the cell into the peritubular fluid. The apical membrane contains the Na+/K+/2Cl- co-transporter (NKCC2) and the K+ channel. The NCKCC2 is responsible for reabsorption Na+, K+ and Cl- from the lumen into the cells of the loop of henle. The K+ channel transports K+ from the cells back into the lumen. Torasemide is transported from the capillaries into the cells of the loop of henle then transported from the cell into the lumen. Torasemide binds to NKCC2 transporter and inhibits it, preventing Na+, K+ and Cl- reabsorption from the lumen. The concentration of these ions builds up in the lumen, decreasing the slope of the concentration gradient between the cells and the lumen. Since water reabsorption is linked to ion reabsorption, water reabsorption is also decreased, resulting in a greater volume of water being excreted in urine. This is relieves symptoms such as swelling/ edema in patients. Side effects frequent urination, headache, cough, sore throat, hearing loss, ringing in your ears, upset stomach, constipation, diarrhea, weakness and excessive thirst may occur when taking torasemide.