Pathways

Lovastatin (also known as Mevacor or Mevinolin) is a statin drug (hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors) that can be used for lowering cholesterol, treating hypercholesterolemia and preventing myocardial infarction and stroke. Lovastatin is produced by fermentation of Aspergillus terreus. HMG-CoA catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol biosynthesis. Lovastatin, like simvastin, is a prodrug. These prodrugs are converted to their active form by in vivo hydrolysis of the lactone ring. The hydrolyzed lactone ring resembles the tetrahedral reaction intermediate produced by HMG-CoA reductase and the bicyclic portions of these compounds bind to the coenzyme A site of the enzyme. The active drug concentrates in the liver during first-pass circulation. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.

Statins are a class of medications that lower lipid levels and are administered to reduce illness and mortality in people who are at high risk of cardiovascular disease. Lovastatin (Mevacor) is a well-tolerated orally-administered synthetic statin that reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride, and very-low-density lipoprotein (VLDL)-cholesterol. It also increases levels of high-density lipoprotein (HDL)-cholesterol. It reduces cholesterol biosynthesis due to the result of a prolonged duration of HMG-CoA reductase inhibition. Reported side effects of lovastatin include constipation, flatulence, dyspepsia (indigestion), abdominal pain, headache, and myalgia (muscle pain). The primary therapeutic mechanism of action of statins is the inhibition of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase in hepatocytes. HMG-CoA reductase catalyzes the conversion of HMG-CoA into mevalonic acid, a precursor for cholesterol biosynthesis. Statins bind reversibly to the active site of HMG-CoA reductase and the subsequent structural change in the enzyme effectively disables it. Due to the resulting decrease in intracellular sterol levels, the ER membrane protein INSIG no longer binds to SREBP cleavage-activating protein (SCAP) which is, itself, bound to the transcription factor sterol regulatory element-binding protein (SREBP). Freed from INSIG, SCAP escorts SREBP to the Golgi apparatus from the ER as cargo in COPII vesicles. At the Golgi membrane, two proteases, S1P and S2P, sequentially cleave the SCAP-SREBP complex, releasing the mature form of SREBP into the cytoplasm. SREBP then translocates to the nucleus where it is actively transported into the nucleoplasm by binding directly to importin beta in the absence of importin alpha. SREBP binds to the sterol regulatory element (SRE) present in the promoter region of genes involved in cholesterol uptake and cholesterol synthesis, including the gene encoding low-density lipoprotein (LDL) receptor (LDL-R). As a result, LDL-R gene transcription increases which then leads to an increased synthesis of the LDL-R protein. LDL-R localizes to the endoplasmic reticulum for transport and exocytosis to the cell surface. The elevated amount of LDL-R results in the binding of more circulating free LDL cholesterol and subsequent internalization via endocytosis. Lysosomal degradation of the internalized LDL cholesterol elevates cellular cholesterol levels to maintain homeostasis.

Metabolites of Lovastatin are predicted with biotransformer.

Loxapine belongs to the class of first generation antipsychotics, a dibenzoxazepine compound in the subclass of tricyclic antipsychotic agents. Loxapine is a dopamine antagonist and serotonin 5-HT2 blocker.

Metabolites of Loxapine are predicted with biotransformer.

Loxapine belongs to the class of first generation antipsychotics, a dibenzoxazepine compound in the subclass of tricyclic antipsychotic agents. Loxapine is a dopamine antagonist and a serotonin 5-HT2 blocker.

Loxoprofen is a nonsteroidal anti-inflammatory agent used to treat pain and inflammation in musculoskeletal conditions and joint disorders. This drug is also an antipyretic and anti-inflammatory medication. Since loxoprofen is a prodrug, it is rapidly metabolized by the carbonyl reductase in the liver to its trans-alcohol form, which is a non-selective inhibitor of cyclooxygenase. This trans-alcohol form 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 convert 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. Salsalate 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. Loxoprofen is administered as an oral tablet.