Pathways

Metabolites of Rivastigmine are predicted with biotransformer.

Rizatriptan is a triptan used to treat migraines with or without aura. Rizatriptan is a second-generation triptan and a selective 5-HT1B and 5-HT1D receptor agonist. Rizatriptan is not indicated for the prophylactic therapy of migraine nor the treatment of cluster headache. Rizatriptan has a weak affinity for other 5-HT1 receptor subtypes (5-HT1A, 5-HT1E, 5-HT1F) and the 5-HT7 receptor but has no significant activity at 5-HT2, 5-HT3, alpha- and beta-adrenergic, dopaminergic, histaminergic, muscarinic or benzodiazepine receptors. Rizatriptan is a selective agonist at the 5-HT1B and 5-HT1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system. It binds to these receptors with high affinity. The exact mechanism of action of rizatriptan has not been fully elucidated; however, several documented pharmacological actions of rizatriptan may contribute to its antimigraine effects. Rizatriptan causes vasoconstriction of intracranial extracerebral blood vessels, which is thought to occur primarily via 5-HT1B receptors. Rizatriptan also inhibits nociceptive neurotransmission in trigeminal pain pathways. It attenuates the release of vasoactive neuropeptides by the trigeminal nerve, which is thought to occur via neurogenic and central 5-HT1D receptors. Rizatriptan inhibited neurogenic dural vasodilation and plasma protein extravasation in animal studies.

Rhamnolipids (RL) consist of a fatty acyl moiety composed of a 3-(3-hydroxyalkanoyloxy)alkaloid acid (HAA) and a sugar moiety composed of one or two rhamnose sugars. Rhamnolipids function as surfactants and virulence factors and are involved in biofilm formation and cell motility. The rhamnose sugar component is produced via the dTDP-L-rhamnose biosynthetic pathway which forms dTDP-L-rhamnose from glucose 6-phosphate (G6P) in five steps. First, glucose 6-phosphate is converted into glucose 1-phosphate (G1P) via the enzyme phosphoglucomutase (AlgC). Second, glucose 1-phosphate is converted into dTDP-D-glucose via the enzyme glucose-1-phosphate thymidylyltransferase (RmlA). Third, dTDP-D-glucose is converted into dTDP-4-dehydro-6-deoxy-D-glucose via the enzyme dTDP-glucose 4,6-dehydratase (RmlB). Fourth, dTDP-4-dehydro-6-deoxy-D-glucose is converted into dTDP-4-dehydro-L-rhamnose via the enzyme dTDP-4-dehydrorhamnose 3,5-epimerase (RmlC). Fifth, dTDP-4-dehydro-L-rhamnose is converted into dTDP-L-rhamnose via the enzyme dTDP-4-dehydrorhamnose reductase (RmlD). The HAA component is synthesized from 3-hydroxyacyl-[acyl-carrier protein] diverted from fatty acid biosynthesis via the enzyme 3-(3-hydroxydecanoyloxy)decanoate synthase (RhIA). The final step in rhamnolipid biosynthesis is the formation of the glycosidic link between the rhamnose sugar component and the HAA component. This is accomplished by two rhamnosyltransferases (RhlB and RhlC) which catalyze sequential glycosyl transfer reactions to first form mono-rhamnolipids (via RhIB) and then di-rhamnolipids (via RhIC). RHlA, RHlB, and RHlC are associated with the inner membrane.

Metabolites of Rocuronium are predicted with biotransformer.

Rofecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a highly selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, rofecoxib exerts its effects by inhibiting the synthesis of prostaglandins involved in pain, fever and inflammation. COX-2 catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGG2) and PGG2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precursor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Rofecoxib antagonizes COX-2 by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Similar to other COX-2 inhibitors such as celecobix and valdecoxib, rofecoxib appears to exploit slight differences in the size of the COX-1 and -2 binding pockets to gain selectivity. COX-1 contains isoleucines at positions 434 and 523, whereas COX-2 has slightly smaller valines occupying these positions. Studies support the notion that the extra methylene on the isoleucine side chains in COX-1 adds enough bulk to proclude rofecoxib from binding. Rofecoxib is 100 times more selective for COX-2 than COX-1. The analgesic, antipyretic and anti-inflammatory effects of rofecoxib occurs as a result of decreased prostaglandin synthesis. The first part of this figure depicts the anti-inflammatory, analgesic and antipyretic pathway of rofecoxib. The latter portion of this figure depicts rofecoxib’s involvement in platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, anuclear cells derived from fragmentation from megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thomboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur. Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Rofecoxib preferentially inhibits COX-2 with little activity against COX-1. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the rare, but severe, adverse cardiovascular effects observed with rofecoxib, which has since been withdrawn from the market.

Rofecoxib (brand name: Vioxx, co-marketed by Monsanto and Merck) is a non-steroidal anti-inflammatory drug (NSAID) that was voluntarily withdrawn from the market in 2004 but is now tentatively used for treatment of osteoarthritis, rheumatoid arthritis, acute pain in adults, and primary dysmenorrhea, as well as acute treatment of migraine attacks with or without auras. It is a selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, rofecoxib exerts its effects by inhibiting the synthesis of prostaglandins involved in pain, fever and inflammation. COX-2 catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGE2) and PGE2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precusor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Rofecoxib inhibits COX-2 via noncompetitive negative allosteric modulation by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Similar to other COX-2 inhibitors, such as celecoxib (Celebrex) and valdecoxib, rofecoxib appears to exploit slight differences in the size of the COX-1 and -2 binding pockets to gain selectivity. COX-1 contains isoleucines at positions 434 and 523, whereas COX-2 has slightly smaller valines occupying these positions. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the adverse cardiovascular effects observed. Rofecoxib (like most "coxib" NSAIDs) is approximately ten times more selective for COX-2 than COX-1. Unlike celecoxib, rofecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. Like other NSAIDs, rofecoxib exhibits anti-inflammatory, analgesic, and antipyretic activity.