Pathways

Simeprevir is a direct-acting antiviral agent that inhibits HCV NS3/4A protease to treat chronic hepatitis C virus (HCV) infection in adults with HCV genotype 1 or 4. Hepatitis C virus lipoviroparticles enter target hepatocytes via receptor-mediated endocytosis. The lipoviroparticles attach to LDL-R and SR-B1, and then the virus binds to CD81 and subsequently claudin-1 and occludin, which mediate the late steps of viral entry. The virus is internalized by clathrin-dependent endocytosis. RNA is released from the mature Hepatitis C virion and translated at the rough endoplasmic reticulum into a single Genome polyprotein. Simeprevir accumulates in the liver after uptake into hepatocytes via solute carrier organic anion transporter family member 1B1. Simeprevir inhibits NS3/4A protease, which is an enzyme that cleaves the heptatitis C virus polyprotein downstream of the NS3 proteolytic site, which generates nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins are required in viral RNA replication, therefore because of the inhibition of their formation, RNA replication cannot occur. Because RNA replication does not occur, the mature virion is unable to form. At higher concentration above their antiviral half-maximal effective concentration (EC50), simeprevir and other NS3/4A inhibitors also restore interferon (IFN)-signaling pathways that are thought to be disrupted by NS3/4A protease and recover innate immune processes. NS3/4A protease cleaves two essential adaptor proteins that initiate signaling leading to activation of IFN regulatory factor 3 and IFN-α/β synthesis, which are mitochondrial antiviral-signaling proteins.

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

Simvastatin, the methylated form of lovastatin, is an inactive lactone that is metabolized in vivo to β,δ-dihydroxy acid, its most potent metabolite. Cytochrome P450 (CYP) enzymes, CYP3A4, CYP3A5, and CYP2C8, have been implicated in this activation step; CYP3A4/5 are responsible for ≥ 80% of simvastatin metabolism while CYP2C8 (not shown in pathway) contributes to ≤ 20% of its metabolism. The simvastatin hydroxy acid inhibits cholesterol synthesis via the mevalonate pathway by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase, a hepatic microsomal enzyme, is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol biosynthesis by this pathway. The active hydroxy acid is structurally similar to the reduced reaction intermediate and competes with HMG-CoA for binding to HMG-CoA reductase. Cholesterol biosynthesis accounts for approximately 80% of cholesterol in the body; thus, inhibiting this process can significantly lower cholesterol levels.

Simvastatin, the methylated form of lovastatin, is an inactive lactone that is metabolized in vivo to β,δ-dihydroxy acid, its most potent metabolite. Cytochrome P450 (CYP) enzymes, CYP3A4, CYP3A5, and CYP2C8, have been implicated in this activation step; CYP3A4/5 are responsible for ≥ 80% of simvastatin metabolism while CYP2C8 (not shown in pathway) contributes to ≤ 20% of its metabolism. The simvastatin hydroxy acid inhibits cholesterol synthesis via the mevalonate pathway by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase, a hepatic microsomal enzyme, is the enzyme responsible for the conversion of HMG-CoA to mevalonic acid, the rate-limiting step of cholesterol biosynthesis by this pathway. The active hydroxy acid is structurally similar to the reduced reaction intermediate and competes with HMG-CoA for binding to HMG-CoA reductase. 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. Simvastatin is a well-tolerated orally-administered synthetic statin that reduces total cholesterol levels, 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 Simvastatin 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 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 the 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 more circulating free LDL cholesterol binding and subsequent internalization via endocytosis. Lysosomal degradation of the internalized LDL cholesterol elevates cellular cholesterol levels to maintain homeostasis. This drug is administered as an oral tablet.

Metabolites of Simvastatin are predicted with biotransformer.