Browsing Pathways

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.

Valproic acid (VPA) is metabolized almost entirely in the liver, via at least there routes: glucuronidation, beta oxidation in the mitochondria, and cytochrome P450 mediated oxidation. The glucuronidation of VPA is mediated by UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7 and UGT2B15. The key CYP-mediated reaction of the VPA metabolic pathway is the generation of 4-ene-VPA by CYP2C9, CYP2A6 and CYP2B6. These three enzymes also catalyze the formation of 4-OH-VPA and 5-OH-VPA. Moreover, CYP2A6 mediates the oxidation of VPA to 3-OH-VPA. Inside the mitochondria, the first step of oxidation is the formation of (VPA-CoA) catalyzed by medium-chain acyl-CoA synthase, followed by the conversion to 2-ene-VPA-CoA through 2-methyl-branched chain acyl-CoA dehydrogenase (ACADSB). 2-ene-VPA-CoA is further converted to 3-hydroxyl-valproyl-VPA (3-OH-VPA-CoA) by an enoyl-CoA hydratase, crotonase (ECSH1) and then 3-OH-VPA-CoA is metabolized to 3-keto-valproyl-CoA (3-oxo-VPA-CoA) through the action of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase. Another route of VPA metabolism in the mitochondria includes the conversion of 4-ene-VPA to 4-ene-VPA-CoA ester catalyzed by ACADSB, followed by a beta-oxidation to form 2,4-diene-VPA-CoA ester. The latter metabolite can furthermore be conjugated to glutathione to form thiol metabolites.

Trandolapril (trade name: Mavik) 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. Trandolapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form trandolaprilat 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.

Tramadol (also named Ultram) is a class of opioid pain medication that used for treating pain. Metabolism of tramadol mainly happened in liver cell. The N-demethylation of tramadol is catalyzed by the cytochrome CYP3A4 and CYP2B6 to form N-Desmethyltramadol, which further metabolized to N,N-Didesmethyltramadol through CYP3A4 and CYP2B6 and to N,O-Didesmethyltramadol through CYP2D6. The O-demethylation of tramadol is catalyzed by the cytochrome CYP2D6 to form O-Desmethyltramadol, which further metabolized to O-Desmethyltramadol glucuronide through UDP-glucuronosyltransferase 2B7 and UDP-glucuronosyltransferase 1-8. O-Desmethyltramadol can also be metabolized to N,O-Didesmethyltramadol through CYP2D6.

Ticlopidine, marketed as Ticlid, is an antiplatelet drug that targets the P2Y12 receptor of platelets. Ticlopidine is taken orally and is a prodrug that 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.

Thioguanine is a purine antimetabolite prodrug closely related to mercaptopurine and similarly inhibits purine metabolism. The thioguanine pathway is shown as a part of the mercaptopurine pathway. Thioguanine exerts cytotoxic effects via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Once in a cell, thioguanine is converted to thioguanosine monophosphate by hypoxanthine-guanine phosphoribosyltransferase. Thioguanosine monophosphate is then phosphorylated to thioguanosine diphosphate, which is converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate. Thiodeoxyguanosine triphosphate is incorporated into DNA causing cytotoxicity. 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.

Tenofovir is a nucleotide analogue used in the treatment of HIV and chronic hepatitis B. It is taken up into the cell and is subsequently phosphorylated first by adenylate kinases and then by nucleoside diphosphate kinases into tenofovir diphosphate. Tenofovir 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, tenofovir causes chain termination, thus preventing viral replication.

Teniposide is a type of chemotherapy drug, derived from the epipodophyllotoxin form the American Mayapple plant. Teniposide is related to etoposide, another anti-cancer drug. It works in a similar way, inhibiting topoisomerase II. This causes single- and double-stranded DNA breaks. These breaks cause cell growth to stop and prevents cancer cells from entering mitosis. It is administered through an intravenous infusion. It is used to treat many cancers such as lymphoma, leukemia (acute lymphocytic), and neuroblastoma.

Temocapril (trade name: Acecol) 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. Temocapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form temocaprilat 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.

Tamoxifen is a selective estrogen modulator (SERM) used in the treatment of estrogen-sensitive breast cancer. Tamoxifen itself only has weak anti-estrogen effects and must be converted into more active metabolites to have therapeutic activity. Metabolism takes place in the liver and is carried out primarily by cytochrome P450 enzymes. Tamoxifen is hydroxylated by CYP2D6 and demethylated by CYP3A4 and CYP3A5, producing the active metabolites 4-hydroxytamoxifen and endoxifen. These metabolites inhibit estrogen binding to estrogen receptors in breast cancer cells, which in turn inhibit tumour growth.