Pathways

Vancomycin is a glycopeptide antibiotic used to treat severe but susceptible bacterial infections such as MRSA (methicillin-resistant Staphylococcus aureus) infections. Administered intravenously, vancomycin is indicated in adult and pediatric patients for the treatment of septicemia, infective endocarditis, skin and skin structure infections, bone infections, and lower respiratory tract infections. Administered orally, vancomycin is indicated in adult and pediatric patients for the treatment of Clostridium difficile-associated diarrhea and for enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains). The bactericidal action of vancomycin results primarily from inhibition of cell-wall biosynthesis. Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix, which forms the major structural component of Gram-positive cell walls. Vancomycin forms hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, preventing the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix. Vancomycin may also alter bacterial-cell-membrane permeability and RNA synthesis. Vancomycin is not active in vitro against gram-negative bacilli, mycobacteria, or fungi.

Valsartan is angiotensin receptor blocker (ARB) which block the action of angiotensin II by binding to the type 1 angiotensin II receptor. Angiotensin II is a critical circulating peptide hormone that has powerful vasoconstrictive effects and increases blood pressure. Valsartan is indicated for the treatment of hypertension to reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the treatment of heart failure (NYHA class II-IV) and for left ventricular dysfunction or failure after myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate. Angiotensin II has many vasoconstrictive effects by binding to angiotensin II type 1 receptors (AT1) in blood vessels, kidneys, hypothalamus, and posterior pituitary. In blood vessels AT1 receptors cause vasoconstriction in the tunica media layer of smooth muscle surrounding blood vessels increasing blood pressure. Blocking this AT1 receptor lowers the constriction of these blood vessels. AT1 receptors in the kidney are responsible for the production of aldosterone which increases salt and water retention which increases blood volume. Blocking AT1 receptors reduces aldosterone production allowing water retention to not increase. AT1 receptors in the hypothalamus are on astrocytes which inhibit the excitatory amino acid transporter 3 from up-taking glutamate back into astrocytes. Glutamate is responsible for the activation of NMDA receptors on paraventricular nucleus neurons (PVN neurons) that lead to thirst sensation. Since AT1 receptors are blocked, the inhibition of the uptake transporter is not limited decreasing the amount of glutamate activating NMDA on PVN neurons that makes the individual crave drinking less. This lowers the blood volume as well. Lastly, the AT1 receptors on posterior pituitary gland are responsible for the release of vasopressin. Vasopressin is an anti-diuretic hormone that cases water reabsorption in the kidney as well as causing smooth muscle contraction in blood vessels increasing blood pressure. Lowering angiotensin II action on activating vasopressin release inhibits blood pressure from increasing. All these effects of valsartan contribute to an overall lowered blood pressure.

Valsartan (also named Diovan) is an antagonist of angiotensin II receptor blockers (ARBs). Valsartan competes with angiotensin II to bind type-1 angiotensin II receptor (AT1) in many tissues (e.g. vascular smooth muscle, the adrenal glands, etc.) to prevent increasing sodium, water reabsorption and peripheral resistance (that will lead to increasing blood pressure) via aldosterone secretion that is caused by angiotensin II. Therefore, action of valsartan binding to AT1 will result in decreasing blood pressure. For more information on the effects of aldosterone on electrolyte and water excretion, refer to the description of the \spironolactone\:http://pathman.smpdb.ca/pathways/SMP00134/pathway or \triamterene\:http://pathman.smpdb.ca/pathways/SMP00132/pathway pathway, which describes the mechanism of direct aldosterone antagonists. Valsartan is an effective agent for reducing blood pressure and may be used to treat essential hypertension and heart failure.

Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. (DrugBank)

Valrubicin (N-trifluoroacetyladriamycin-14-valerate), also known as Valstar, is a chemotherapy drug from the anthracycline class. It is a semisynthetic analog of doxorubicin. Valrubicin has a more rapid uptake in the tumors than doxorubicin. Moreover, it does not have the preferential negative ion binding in cell membranes thought to be the cause for the cardiac toxicity of doxorubicin. This drug is used to treat BCG-resistant bladder carcinoma and is administered directly in the bladder (intravesical). Valrubicin affects a variety of interrelated biological functions, mostly the one involving the nucleic acid metabolism. It does DNA intercalation, then, it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests the cell cycle in the G2 phase. A principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II. This drug inhibits the DNA topoisomerase by binding to its 2-alpha part. This action cause DNA strand breaks, partial unwinding/uncoiling of DNA, and inhibition of DNA and RNA synthesis. DNA damage leads to programmed cell death (apoptosis) of the cancer cells, preventing the growth and proliferation of cancer in patients.

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.