Browsing Pathways

Irinotecan is a medication commonly sold as Camptosar, used to stop the growth of cancer cells, and to stop the spread of cancer cells in the human body. Specifically cancers of the rectum and of the colon. Commonly used in combination with chemotherapy. Irinotecan works through its active metabolite, SN-38, which inhibits the action of topoisomerase I. This enzyme is responsible for creating single-strand breaks in DNA during replication. These single-strands are reversible. SN-38 and Irinotecan binding to topoisomerase I-DNA complex results in the prevention of religation the DNA strand mentioned above, which creates double-strand DNA breakage. This breakage leads to cell death. Irinotecan is taken orally, but can also be injected.

Lamivudine (2'-deoxy-3'-thiacytidine, 3TC) is a pyrimidine analog reverse transcriptase enzyme inhibitor used to treat human immunodeficiency virus type I (HIV-1), HIV-2, and Hepatitis B. When metabolized to its active triphosphate form, it competes with deoxycytidine triphosphate for binding to reverse transcriptase, resulting in chain termination when incorporated into the viral DNA. Lamivudine may enter the cells by passive diffusion or by active transported via SLC22A1, SLC22A2, and SLC22A3. Intracellularly, it is phosphorylated to its active triphosphate from via deoxycytidine kinase (3TC to 3TC-monophosphate), followed by cytidine monophosphate/deoxycytidine monophosphate kinase (3TC-monophosphate to 3TC-diphosphate), then 3'-phosphoglycerate kinase or nucleoside diphosphate kinase (3TC-diphosphate to 3TC-triphosphate). Dephosphorylation can occur via phosphatases or salvage pathways. Lamivudine is actively transported out of cell by efflux transporters ABCB1, ABCC1, ABCC2, ABCC3, ABCC4 and ABCG2 and primarily excreted unchanged in the urine.

Lansoprazole, sold as Prevacid, is a proton pump inhibitor (PPI) class drug that suppresses the final step in gastric acid production. In this pathway, lansoprazole is taken orally and is oxidized in the stomach to form the active metabolite of lansoprazole. 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. Lansoprazole 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.

Levomethadyl Acetate (also known as levacetylmethadol or levo-α-acetylmethadol) (LAAM), is a synthetic opioid structurally similar to methadone. It is an opioid agonist that has been used as an analgesic and to treat opioid dependence. Levomethadyl Acetate is metabolized by cytochrome P450 3A4 in two N-demethylation reactions to nor-levomethadyl acetate (nor-LAAM) and subsequently to dinor-levomethadyl acetate (dinor-LAAM).

Lidocaine exerts its local anaesthetic effect by blocking voltage-gated sodium channels in peripheral neurons. Lidocaine diffuses across the neuronal plasma membrane in its uncharged base form. Once inside the cytoplasm, it is protonated and this protonated form enters and blocks the pore of the voltage-gated sodium channel from the cytoplasmic side. For this to happen, the sodium channel must first become active so that so that gating mechanism is in the open state. Therefore lidocaine preferentially inhibits neurons that are actively firing.

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.

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.

Moexipril (trade name: Univasc) 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. Moexipril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form moexiprilat 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.

Morphine 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.

Mycophenolic Acid (MPA) is an immunosuppressive agent that acts as a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). It is available as a prodrug, Mycophenolate mofetil (MMF), which is a 2-morpholinoethyl ester with improved bioavailability. After absorption, MMF is hydrolyzed to MPA and N-(2-carboxymethyl)- morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine by the carboxylesterases CES-1 (in the liver only) and CES-2 (in the liver and intestine). The morpholine metabolites are excreted in the urine. MPA is glucuronidated by UDP glucuronosyl transferases (UGTs) UGT1A7, UGT1A8, UGT1A9 and UGT1A10 to MPA-7-O-glucuronide, which is excreted in the urine. Other metabolites of MPA include MPA-acyl glucoronide, which is formed by UGT2B7, and 6-O-desmethyl-MPA, which is formed by the CYP enzymes CYP3A4, CYP3A5 and CYP2C8. MPA enters hepatocytes by the organic anion transport proteins (OATPs) SLCO1B1 and SLCO1B3. MPA and its metabolites are excreted in the bile via the ABCC2, ABCG2, and ABCB1 proteins.