Stable Isotope Usage in Drugs Industry

The breaking of carbon-hydrogen bonds is a common features of drug metabolism, for example during oxidation. Breaking of an analogues carbon-deuterium bond can be more difficult, and so decrease the rate of metabolism. Therefore, replacement of hydrogen with deuterium in drug molecules can lead to significant alterations in this metabolism and thereby cause beneficial changes in the biological effects of drugs, such as their pharmacokinetics by decreasing their rate of metabolism allowing less frequent dosing.

Deuterium labeling has effect of lowering toxicity by reducing the formation of a toxic metabolite.

 

References:>

1.     S. L. Harbeson, R. D. Tung, Deuterium medicinal chemistry: A new approach to drug discovery and development, MEDCHEM NEWS No. 2, 2014.

2.     G. S. Timins, Deuterated drugs; where are we now?, Expert opin ther pat., 2014

Stable Isotope Application in Determination of fat amount in the human body

Determining the amount of fat in the human body can be done by measuring total body water (TBW) with isotopes. The human body can be thought of as being composed of two categories: fat mass, and fat-free mass. There is no water in fat mass, whereas 73–80% of fat free mass consists of water. The fat-free mass of a newborn baby contains 80% water, and this gradually decreases to 73% in adults. This means fat-free mass can be determined by measuring TBW and then using an appropriate hydration factor. Hydration factor was developed to be the most effective way to ensure the water you drink provides your body with overall hydration. There are many methods for determining hydration status, including monitoring body mass changes, measuring various blood markers, and analysis of urine. That urine analysis has been shown to be most valid and reliable method for determining moderate changes in fluid balance.

The deuterium dilution technique involves measuring a person’s saliva and/ or urine just before they consume a dose of deuterium labeled water and repeating the process 3 to 5 hours later. The increased level of deuterium shows in the person’s saliva and urine samples. The deuterium is evenly distributed throughout the body after 3 to 5 hours. The person’s pre-dose samples of urine or saliva are compared with the post-dose samples to calculate TBW, fat-free mass and ultimately the amount of fat in the body. Body composition is a good indication of health. Too much fat or too little fat-free mass raises the risk of serious health conditions.

References:

1. How isotope techniqes help nutrition, IAEA Bulletin 55-1-March 2014.

2. Body composition by hydrometry, ME Valencia1, H Alema´n-Mateo1, International Journal of Obesity 2003.

 

 

Stable Isotope effects on Chemical mechanism

The use of kinetic isotope effects in interpretation of organic reaction mechanisms has undergone a remarkable development. Nowadays, Kinetic isotope effect is considered to be one of the most essential and sensitive tools for the study of reaction mechanisms.

Kinetic isotope effect (KIE) refers to the change in the rate of a chemical reaction upon substitution of an atom in the reactants with one of its isotopes.

Primary kinetic isotope effect: may be found when a bond to the isotopically labeled atom is being formed or broken. The rate of a reaction involving a C–H bond is typically 6–10 times faster than the corresponding C–D bond.

 

Secondary kinetic isotope: This type of isotope effect is significant when the atom to which the isotopic atom is bonded undergoes a hybridization change. Which, change in the hybridization during the formation of the transition state would lead to considerable KIE on the corresponding reaction rate.

 

For example, kinetic isotope effects can be used to reveal whether a nucleophilic substitution reaction follows a unimolecular (S_N1) or bimolecular (S_N2) pathway.

 

1. U. Maitra, J. Chandrasekhar, Use of Isotopes for Studying Reaction Mechanisms, Secondary Kinetic Isotope Effect, Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012.

2. G. Hong, Sh. Zhang, Advances in Kinetic Isotope Effect Measurement Techniques for Enzyme Mechanism Study, Molecules, 2013, Vol. 18, 9278-9292.

3. P. J. SMITH, A. N. BOURNS, Isotope effect studies on elimination reactions, The mechanism of the bimolecular elimination reaction of arylethylammonium ions, CANADIAN JOURNAL OF CHEMISTRY, Vol. 48. 1970.

Stable Isotope effects on Cancer Cells

D2O AS A STABLE ISOTOPE shows a variety of different biological activities from normal water. It is shown to be active in various cancer cell lines in vitro and in vivo.

D2O AS A STABLE ISOTOPE effectively inhibited the growth and colony formation of three different human pancreatic carcinoma cell lines. D2O AS A STABLE ISOTOPE AS A STABLE ISOTOPE is also active against pancreatic cancer cells in vitro. D2O AS A STABLE ISOTOPE AS A STABLE ISOTOPE has been reported to exert antineoplastic effects in vitro and in vivo. It delayed the growth of human oropharyngeal squamous cell cancer and colon cancer in nude mice. D2O AS A STABLE ISOTOPE is a useful agent against human pancreatic carcinoma cells in vitro, a fact that makes it a potential candidate for the treatment of pancreatic tumors.

 

Reference:

J. Hartmann, Y. Bader, Z. Horvath, P. Saiko, M. Grusch, C. Illmer, S. Madlener, M. F. Szekeres, N. Heller, R. Alken, T. Szekeres, 2005, Effects of Heavy Water (D2O AS A STABLE ISOTOPE) on Human Pancreatic Tumor Cells, Anticancer Research, 25, 3407-3412

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stable isotope info

Isotopes are variants of a particular chemical element such that, while all isotopes of a given element have the same number of protons in each atom, they differ in neutron number.

• The short relaxation time of deuterium of the spin 1 (quadrupole) provides substantial sensitivity for nuclear magnetic resonance spectroscopy (MRS).

• When D2O is administered in a bolus fashion to a specific tissue or organ in vivo, the deuterium MRS intensity time course can be analyzed to measure the rate of blood flow and tissue perfusion.

•FDA responds to Teva’s NDA with complete response letter for Huntington’s chorea drug

•SD-809 is the first deuterated product that the FDA has reviewed.

•FDA just asked Teva to analyze blood levels of certain metabolites, which are not novel and are similar in subjects who take either tetrabenazine or deutetrabenazine.

•The FDA has requested no further clinical trials.

•Teva will continue to work closely with the FDA to bring SD-809 to the market as quickly as possible,” said Michael Hayden, M.D., Ph.D., Teva’s president of global research and development and CSO