Browsing Pathways

Doxepin is a tricyclic antidepressant (TCA) that can be used for treating major depressive disorder and sleep maintenance. Doxepin is metabolized by cytochrome P450 2C19, 1A2, 2C9, 3A4 to form N-desmethyldoxepin, and form (E)-2-hydroxydoxepin by solely cytochrome P450 2D6 in ER of liver.

Venlafaxine (also named as Effexor or Elafax) is an antidepressant medication, which belongs to the class of serotonin-norepinephrine reuptake inhibitor (SNRI). Venlafaxine is well absorbed into the circulation system. Venlafaxine is also metabolized to N-desmethylvenlafaxine. The N-demethylation is catalyzed by CYP3A4 and CYP2C19. N-desmethylvenlafaxine is a weaker serotonin and norepinephrine reuptake inhibitor. Both O-desmethylvenlafaxine (as potent a serotonin-norepinephrine reuptake inhibitor) and N-desmethylvenlafaxine are further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to a minor metabolite N,O-didesmethylvenlafaxine that is further metabolized into N,N,O-tridesmethylvenlafaxine or excreted as N,O-didesmethylvenlafaxine gucuronide. Later on, O-desmethylvenlafaxine is exported without any change in chemical structure. Venlafaxine is exported via two transporters: Multidrug resistance protein 1 and ATP-binding cassette sub-family G member 2.

Sorafenib is a drug that belongs to the antineoplastics drug class, which is the drug class relating to the treatment of cancer, specifically renal, hepatic and thyroid cancers. This drug works by stopping cancerous tumour progress and stopping therapy replication pf potentially malignant cells. It does this by inhibiting protein synthesis, as we will explore in the pathway. Sorafenib is administered orally, in a tablet form taken twice daily without food. Once ingested, sorafenib finds itself in the endoplasmic reticulum membrane , where it inhibits cytochrome P450 2B6, cytochrome P450 2C8, cytochrome P450 2C9 and UDP-glucuronosyltransferase 1-1. Sorafenib is also catalyzed, with the help uridine diphosphate glucuronic acid and the enzyme UDP-glucuronosyltransferase 1-9 to sorafenib b-D-glucuronide with a by-product of uridine 5’-diphosphate. Sorafenib also undergoes a transformation without the use of catalytic enzymes and becomes sorafenib metabolite M4 and subsequently becomes sorafenib metabolite M5. In another reaction, sorafenib teams up with water and oxygen, using cytochrome P450 3A4 to create sorafenib N-oxide and hydrogen peroxide. Sorafenib N-oxide then undergoes two more reactions, one where it becomes sorafenib N-oxide glucuronide, and another where it becomes sorafenib metabolite M1. Sorafenib metabolite M1 is also attached to another reaction, as sorafenib creates sorafenib metabolite M3, sorafenib metabolite M1 is also created from this metabolite.

Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is extensively metabolized in the liver by the cytochrome p450 enzymes CYP2C8 and CYP2C9 to para-hydroxy rosiglitazon, ortho-hydroxy rosiglitazone and N-desmethyl rosiglitazone. N-desmethyl rosiglitazone is the major metabolite and is further metabolized to N-desmethyl-p-hydroxyrosiglitazone, N-desmethyl glucuronide rosiglitazone and N-desmethyl-O-hydroxy rosiglitazone. Both para-hydroxy rosiglitazon and ortho-hydroxy rosiglitazone are excreted as sulfated or glucuronidated metabolites.

Adefovir dipivoxil is an ester prodrug of adefovir, a nucleotide analogue used in the treatment of chronic hepatitis B. Adefovir dipivoxil is taken up into the liver cell and is cleaved into adefovir by intracellular esterases. Adefovir is subsequently phosphorylated first by adenylate kinases and then by nucleoside diphosphate kinases into adefovir diphosphate. Adefovir diphosphate is an analogue of deoxyadenosine triphosphate (dATP) and competes with dATP for binding to the viral DNA polymerase and subsequent incorporation into the growing DNA strand. Once incorporated into the DNA, adefovir causes chain termination, thus preventing viral replication.

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

Methadone exerts its analgesic by acting on the mu-opioid receptor of sensory neurons. Binding to the mu-opioid receptor activates associated G(i) proteins. These subsequently act to inhibit adenylate cyclase, reducing the level of intracellular cAMP. G(i) also activates potassium channels and inactivates calcium channels causing the neuron to hyperpolarize. The end result is decreased nerve conduction and reduced neurotransmitter release, which blocks the perception of pain signals. Methadone further acts as an antagonist at the NMDA receptor, reducting calcium influx and neuronal excitability.

Mercaptopurine is a purine antimetabolite prodrug that exerts cytotoxic effects via three mechanisms: via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA, inhibition of de novo synthesis of purine nucleotides, and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Mercaptopurine travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is then converted to thioguanosince diphosphate through a series of metabolic reactions that produces the metabolic intermediates, thioinosine 5’-monophosphate, thioxanthine monophosphate, and thioguanosine monophosphate. Thioguanosine diphosphate is then converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate, which is incorporated into DNA. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells. Finally, de novo synthesis of purine nucleotides is inhibited by the methyl-thioinosine 5’-monophosphate metabolite, which inhibits amidophosphoribosyl-transferase, the enzyme that catalyzes one of the first steps in this pathway.

Rabeprazole is a drug that belongs to the anti secretory drug class. It is used as an anti-ulcer medication, and helps relieve gastric acid reflux, gastric irritation and gastric pain. It inhibits the proton pump action of ATPase, which blocks the final step of gastric acid secretion. The pathway begins in the parietal cell in the stomach, where rabeprazole and a hydrogen ion use the active metabolite in rabeprazole —rabeprazole thioether — to inhibit potassium-transporting ATPase at the secretory surface of the gastric parietal cell. Now in the gastric endothelial cell, these secretory surfaces are inhibited by rabeprazole and by G-Protein signalling cascade through somatostatin receptor type 4, which is activated by somatostatin. At the same time, potassium-transporting ATPase is activated by the G-protein signalling cascade, through histamine H2 receptor, gastrin/cholecystokinin type B receptor, and muscarinic acetylcholine receptor M3 which are activated by histamine, gastrin and acetylcholine, respectively. The potassium transporting ATPase also converts water and ATP to a phosphate molecule and ADP. Alongside the transporters, potassium is brought into the cell. Carbonic anhydrase 1 uses water and carbon dioxide to create hydrogen carbonate and a hydrogen ion, which are both transported out of the endothelial cell, into the gastric lumen. A chloride ion is transported into the gastric endothelial cell through a chloride anion exchanger and is transported out of the cell through a chloride intracellular channel protein 2, back into the gastric lumen.

Ibuprofen is a very common NSAID drug used to treat pain and inflammation. This includes headaches, muscle pain and fever. It is sold under the brand name Advil or Motrin. Ibuprofen is typically ingested orally, although in the USA an intravenous version can be used. It inhibits cyclooxygenase (COX) non-selectively. This enzyme is responsible for the creation of prostaglandins, which allow pain to be felt. Inhibiting COX makes prostaglandin creation more sparse, thus resulting in less pain for the patient using ibuprofen. Arachdonic acid is converted into prostaglandin H2 by using cytosolic prostaglandin G/H synthase (COX). These enzymes are available as COX1 and COX2, and are encoded by PTGS1 (COX1) and PTGS2 (COX2). Ibuprofen may also inhibit fatty acid amide hydrolase (FAAH), which results in the activation of antinociceptive axis, which then metabolizes the endocannabinoid anandamide.