Pathways

Isradipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension. Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. It is structurally related to felodipine, nifedipine, and nimodipine and is the most potent calcium-channel blocking agent of the DHP class. Isradipine binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and arterial smooth muscle cells. Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells. Some side effects of using isradipine may include headache, dizziness, flushing, and tiredness.

Itraconazole is an antifungal drug used primarily in the treatment of immunocompromised patients or fungal infection that Fluconazole cannot deal with, such as the fungus Candida galbrata, which has a resistance to Fluconazole. Itraconazole targets the area of infection which can be anywhere in the system, however immunocompromised patients have an increased chance of infection in the brain. It is also more likely to be used for pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis, but not much is known of the fungi species in those infections. Itraconazole once in the blood travels to the target location. In the brain it can use the transporter solute carrier organic anion transporter family member 2B1 in order to carry it across the blood-brain barrier. Once in the target area Itraconazole inhibits the enzyme Cytochrome P450 51 or Lanosterol 14-alpha demethylase in the fungal cell. It does this by binding the free nitrogen atom located on the azole ring to an iron atom of Lanosterol 14-alpha demethylase. This enzyme catalyzes the reaction of lanosterol with 3 oxygen and 3 NADPH to become 4,4-Dimethylcholesta-8,14,24-trienol with byproducts of formic acid, 4 hydrogen ions, 4 water, and 3 NADP+. This reaction is the first step in the biosynthesis of ergosterol which resides on fungi cell membranes and is integral to cell membrane integrity, similarly to cholesterol in animal cells. With this process inhibited by Itraconazole, the fungal cell cannot produce more fungi cells, and has increased membrane permeability causing leakage of cellular contents.

Itraconazole is an antifungal drug used primarily in the treatment of immunocompromised patients or fungal infection that Fluconazole cannot deal with, such as the fungus Candida galbrata, which has a resistance to Fluconazole. Itraconazole is taken mainly in a pill form. The oral bioavailability of itraconazole is only 55% and is best when taken with food. Itraconazole is 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 there, it travels to the liver and is transported in via P-glycoprotein. On the membrane of the endoplasmic reticulum Itraconazole will slightly inhibit Lanosterol 14-alpha demethylase, the first step in steroid biosynthesis and a very similar enzyme to what it inhibits in fungal yeast cells.It is highly selective for fungal Lanosterol 14-alpha demethylase, but will still inhibit it in humans to a degree. It also inhibits Cytochrome P450 3A5, Cytochrome P450 3A7, Cytochrome P450 3A4, Cytochrome P450 2B6, and Cytochrome P450 2E1, which are similar to Lanosterol 14-alpha demethylase. This all produces adverse but not lethal effects. Itraconazole is then metabolized in the endoplasmic reticulum of the liver into many unknown metabolites, but mainly into hydroxyitraconazole. This metabolite along with the remaining Itraconazole that was not metabolized are transported back into the blood where they travel to the kidney to be excreted renally. 3%-18% is transported into the bile ducts where it goes to the intestines to be excreted through the feces. Only about 0.03% of the dose is excreted as Itraconazole. 40% is excreted as metabolites.

Metabolites of Ivacaftor are predicted with biotransformer.