Browsing Pathways

Clopidogrel, marketed as Plavix, is an antiplatelet drug that targets the P2Y12 receptor of platelets. Clopidogrel is taken orally as a prodrug, and must be metabolically activated before it can be effective. It first enters the liver and enters the endoplasmic reticulum where it is metabolized to form the active metabolite. First, it is catalyzed by cytochromes P450 2C19, 2B6 and 1A2 into 2-oxoclopidogrel. Secondly, it is processed by cytochromes P450 2B6, 2C9, 2C19, 3A4, 3A5, and serum paraoxonase/arylesterase 1 into the active metabolite of clopidogrel. The active metabolite of clopidogrel then enters the blood stream, where it binds irreversibly to the P2Y purinoreceptor 12 on the surface of platelet cells, preventing ADP from binding to and activating it. Clopidogrel prevents the activation of the Gi protein associated with the P2Y12 receptor from inactivating adenylate cyclase in the platelet, leading to a buildup of cAMP. This cAMP then activates calcium efflux pumps, preventing calcium buildup in the platelet, which would cause activation, and later, aggregation.

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.

Cyclophosphamide is an alkylating agent used in the treatment of certain cancers. Following absorption, cyclophosphamide is converted into 4-hydroxyphosphamide by a variety of cytochrome P450 isozymes in the liver. 4-Hydroxyphosphamide is more soluble than cyclophosphamide and is the primary form of the drug that is transported in blood. 4-Hydroxyphosphamide crosses the plasma membrane of the cancer cell and spontaneuosly forms aldophosphamide. This is a reversible reaction. Aldophosphamide can decompose into acrolein and phosphoramide mustard. Phosphoramide mustard is the active alkylating agent and forms alkyl adducts with DNA through a phosphoramide aziridinium intermediate. Alkylation of DNA causes DNA damage and eventually cell death.

Desipramine is a tricyclic antidepressant that exerts its therapeutic effects by inhibiting norepinephrine and serotonin reuptake in the brain. It does so by competing for the same binding site as norepinephrine on the sodium-dependent noradraneline transporter (SLC6A2) and by competing with serotonin for binding to the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of both norepinephrine and serotonin in their respective synapses and reverses the state of low concentrations of both neurotransmitters found in depression. Higher concentrations of norepinephrine and serotonin have also been shown to have long-term neuromodulatory effects. Binding of these neurotransmitters to their respective receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.

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.

Doxorubicin is an anthracycline antibiotic used as a cancer chemotherapy drug. The major metabolic route of doxorubicin metabolism is two-electron reduction to doxorubicinol. A second route is one-electron reduction resulting in a doxorubicin-semiquinone, which can be undertaken by NADH dehydrogenases in the sarcoplasmic reticulum or mitochondrion, or nitric oxide synthases, NADPH dehydrogenase, or xanthine oxidase. Reactive oxygen species are formed when the semiquinone is re-oxidized back to doxorubicin. The reactive oxygen species are thought by some to be responsible for the drug's effects and cardiotoxicity, and can be deactivated by glutathione peroxidase, catalase, and superoxide dismutase. A third and minor metabolic route involves deglycosidation and results in the formation of doxirubicinol hydroxyaglycone. Approximately 50% of doxorubicin is eliminated unchanged from the body.

Enalapril (trade name: Vasotec) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Enalapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form enalaprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.

Esomeprazole, sold as Nexium, is a proton pump inhibitor (PPI) class drug that suppresses the final step in gastric acid production. In this pathway, esomeprazole is taken orally and is oxidized in the stomach to form the active metabolite of esomeprazole. This active metabolite then binds covalently to the potassium-transporting ATPase protein subunits, found at the secretory surface of the gastric parietal cell, preventing any stimulus. Because the drug binds covalently, its effects are dose-dependent and last much longer than similar drugs that bind to the protein non-covalently. This is because additional ATPase enzymes must be created to replace the ones covalently bound by pantoprazole. Esomeprazole is used to manage gastroesophageal reflux disease, to prevent stomach ulcers, and can be used to help treat the effects of a H. pylori infection.

Etoposide is a medication commonly sold as Vepesid, or Etopophos. It is a type of chemotherapy. It is used to treat many types of cancers, including nonlymphocytic leukemia and testicular cancer. Etoposide is semisynthetic and a derivative of the podophyllotoxins which is an epipodophyllotoxin. This substance is found in the root of the American Mayapple plant. The way this substance works is by inhibiting topoisomerase II, which inhibits DNA synthesis. This breaks the catalytic cycle of topoisomerase II, and after a while overwhelms the cell. This can cause a death pathway, killing the cancer cell. Etoposide is administered by a doctor, through intravenous infusion.

Felbamate is metabolized in the liver. One route of metabolism consists of the hydroxylation to 2-hydroxyfelbamate or p-hydroxyfelbamate, which is catalyzed by CYP2E1 and CYP3A4. Moreover, felbamate can be transformed to 2-phenyl-2-propanediol monocarbamate. This metabolite is then converted to 3-carbamoyl-2phenylpropionaldehyde via alchol dehydrogenase 1A, which in turn can be transformed into three possible metabolites: atropaldehyde, 3-carbamoyl-2-phenylpropionic acid (catalyzed by the dimeric NADP-preferring aldehyde dehydrogenase), and 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one. The latter is further converted by the alcohol dehydrogenase 1A to 5-phenyl-1,3-oxazinane-2,4-dione, which is subsequently transformed to 3-carbamoyl-2-phenylpropionic acid.