Pathways

Polythiazide is an oral diuretic drug that acts in the kidney, specifically in the distal convoluted tubule of the nephron. It is used to decrease edema and decrease blood pressure. In the distal convoluted tubule (DCT), the regulation of ions such as sodium, potassium, calcium, chloride, and magnesium occurs. In epithelial cells of the DCT, the basolateral membrane consists of the Na+/K+ ATPase, which pumps Na+ into the interstitium-blood area and K+ into the epithelial cell; the Na+/Ca2+ exchanger, which pumps Na+ into the cell and Ca2+ into the interstitium-blood; and the chloride transporter which transports chloride into the interstitium-blood. The apical membrane contains a calcium channel that transports calcium from the lumen into the epithelial cell, a potassium channel that transports K+ out of the epithelial cell, and a Na+/Cl- cotransporter which transports Na+ and Cl- into the epithelial cell. Polythiazide targets this Na+/Cl- cotransporter. Polythiazide is transported from the blood into the epithelial cells, then is transported into the urine through the multidrug-resistant associated protein-4. In the lumen, it has access to the Na+/Cl- transporter and inhibits it preventing Na+ reabsorption. The inhibition of Na+ reabsorption results in a low cytosolic concentration of Na+ and increases the solute concentration of the lumen. This decreases the lumen-epithelial cell concentration gradient and as a result, less water would be reabsorbed from the urine. This effect is valued in conditions such as hypertension because it allows more water to be excreted in urine rather than be absorbed in the blood which increases blood volume. Side effects such as low blood sodium/potassium, weight loss, nausea, vomiting, cramping, diarrhea, constipation, dizziness, vertigo, yellowing of skin or eyes (jaundice), numbness and tingling, sensitivity to light, headache, rash, hives, muscle spasm, high blood sugar, weakness or restlessness can occur from taking polythiazide. This drug is administered as an oral tablet.

Polythiazide is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Polythiazide passes through the liver and is then excreted from the body mainly through the kidney.

Ponatinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Ponatinib is considered a third generation BCR-ABL inhibitor (Imatinib being the progenitor) due to its effectiveness against the T315I mutation in BCR-ABL. For greater detail of some of the signalling pathways inhibited by BCR-ABL inhibition, refer to the pathway titled BCR-ABL Action in CML Pathogenesis.

Metabolites of Ponesimod are predicted with biotransformer.