Browsing Pathways

Acetaminophen (APAP) is metabolized primarily in the liver. Glucuronidation is the main route, accounting for 45-55% of APAP metabolism, and is mediatied by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver and UGT1A10 in the gut. APAP can also by metabolized via sulfation, accounting for 30-35% of the metabolism. In the liver, this step is catalyzed by the sulfotransferases SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1. Moreover, APAP can also be activated to form the toxic N-acetyl-p-benzoquinone imine (NAPQI) under the mediation of CYP3A4, CYP2E1, CYP2D6 CYP1A2, CYP2E1 and CYP2A6.

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.

Artemether is a semisynthetic derivative of artemisinin, a phytoconstituent that acts as a short-acting antimalarial agent and is used to treat uncomplicated Plasmodium falciparum malaria. Artemisinin derivatives kill parasites more rapidly than conventional antimalarial drugs, and are active against both the sexual and asexual stages of the parasite cycle. However due to their short half-life (and to prevent resistance development) artemisinin compounds are often combined with long-acting antimalarial drugs. Artemeter is administered orally and as an oil-based intramuscular injection. The antimalarial activity of artemether and other artemisinin derivatives is a result of the peroxide bridge found in the active metabolite dihydroartemisinin. Dihydroartemisinin is formed from the rapid demethylation of artmether via CYP3A4 and CYP3A5. It then undergoes glucuronidation catalyzed by the UDP-glucuronosyltransferases UGT1A9 and UGT2B7 into inactive metabolites that are eliminated in the bile.

Azathioprine 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. Azathioprine is first converted _in vivo_ to mercaptopurine in the liver. Mercaptopurine then travels through the bloodstream and is transported into cells via nucleoside transporters. Mercaptopurine is 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.

Benazepril (trade name: Lotensin) 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. Benazepril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form benazeprilat 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.

Capecitabine is a fluoropyrimidine anticancer drug. After absorption, it is metabolized in the liver to the intermediate 5’-deoxy-5-fluorouridine, which is subsequently converted into 5-fluorouracil (5-FU) by intracellular thymidine phosphorylase. 5-FU exerts cytotoxic effects on the cell by direct incorporation into DNA and RNA as well as by inhibiting thymidylate synthase. Since thymidine phosphorylase is present at 3-10 fold higher concentration in cancer cells compared normal cells, capecitabine’s cytotoxic effect is selective for cancer cells.

Carbamazepine is a drug used in the treatment of epilepsy, bipolar disorder, trigeminal neuralgia, and other psychiatric disorders. Carbamazepine is almost entirely metabolized in the liver, with the primary metabolic pathway being conversion to 10,11-epoxycarbamazepine. Ring hydroxylation to 2-hydroxycarbamazepine and 3-hydroxycarbamazepine represent a minor metabolic route, presumably though a carbamazepine 2,3-epoxide intermediate. Potential bioactivation occurs via CYP3A4-mediated secondary oxidation of 2-hydroxycarbamazepine to the potentially reactive carbamazepine iminoquinone and of 3-hydroxycarbamazepine to form other reactive metabolites. Radicals can also be formed from metabolism of 3-hydroxycarbamazepine by myeloperoxidase. Oxcarbazepine, an anticonvulsant used primarily in the treatment of epilepsy, is converted to 10,11-dihydroxycarbamazepine via 10-hydroxycarbazepine.

Cilazapril (trade name: Dynorm, Inhibace, Vascace) 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. Cilazapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form cilazaprilat 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.

Cimetidine, sold as Tagamet, is a compound related to histamine. It is a H2 antagonist drug, also called H2RAs or H2 blockers, and was the first of this class to be discovered. H2 antagonist drugs compete with histamine to bind to the histamine H2-receptors found on the basolateral membrane of gastric parietal cells. This blocks histamine effects, resulting in reduced gastric acid secretion and a reduction in gastric volume and acidity. Cimetidine also helps to block pepsin and gastrin output, and due to the inhibition of gastric acid secretion, it is typically used to treat heartburn and ulcers. Cimetidine also blocks the activity of cytochrome P-450 enzymes CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4, which may affect the metabolism of other drugs.

Citalopram is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin 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.