Principle of Deuterated Drugs
Deuterium is an isotope of hydrogen, where its atomic nucleus contains one additional neutron compared to hydrogen, giving it an atomic mass that is twice that of hydrogen. Deuterium is non-radioactive and exists stably in nature in the form of deuterium oxide, with an abundance of approximately 0.0156%. Because the spatial structure of C-D bonds is similar to C-H bonds, the stereochemistry and spatial flexibility of deuterated molecules remain unchanged after deuteration. As a result, compounds modified with deuterium can retain their biochemical efficacy and selectivity.
Deuteration can extend a drug’s duration of action in the body, reduce the required dosage, improve efficacy, and reduce toxic reactions. This is primarily due to the kinetic isotope effect (KIE). KIE is a phenomenon where molecules with isotopic substitutions exhibit different reaction rates. Kinetic isotope effects are used to determine the reaction mechanism by identifying rate-limiting steps and transition states, typically using NMR to detect isotopic positions or GC/MS to track changes in molecular weight. In KIE experiments, atoms are substituted with their isotopes, and the change in reaction rates is observed. The effect is characterized by the ratio of the rate constants, kH/kD.
The isotopic effect of heavier atoms, such as carbon, oxygen, nitrogen, sulfur, and bromine, is much smaller, typically ranging between 1.02 and 1.10. However, due to the significant mass difference between hydrogen and deuterium, substituting key hydrogens with deuterium can have a significant impact on the reaction rate. Since C-D bonds have higher bond energies, breaking a C-D bond requires more energy than breaking a C-H bond. As the breaking of C-H bonds is a crucial step in the metabolic process of compounds, replacing C-H bonds with the more stable C-D bonds may reduce the drug metabolism rate.
Development Stages of Deuterated Drugs
As early as 1961, multiple research groups discovered that drugs could exhibit different pharmacokinetic characteristics before and after deuteration, marking the initial conceptualization of introducing deuterium sources into drugs. For example, Elison and colleagues studied the impact of deuterated morphine on enzymatic oxidative metabolism, while Foreman and others found that deuterated tyramine had a pharmacological effect duration twice as long as the non-deuterated version.
However, researchers did not observe significant pharmacokinetic and pharmacological advantages from these early deuterated drugs. Factors such as underdeveloped chemical synthesis methods for deuterated drugs and the scarcity of deuterium sources limited progress, so these early studies remained at the in vitro and animal study stages, with no deuterated drugs advancing to clinical research. It wasn’t until the 2000s, with advancements in deuterated drug synthesis technology, increased availability of deuterium sources, deeper exploration of pharmacological mechanisms, and clear patent protection for deuterated drugs, that research and development in this area gained renewed attention.
Today, deuterated drugs are becoming a hot topic in new drug development. Many pharmaceutical companies worldwide are actively developing deuterated drugs, with some already in Phase III clinical trials or new drug market application stages.
In April 2017, the U.S. Food and Drug Administration (FDA) approved the world’s first deuterated drug-Teva’s deuterated deutetrabenazine tablets-for the treatment of Huntington’s disease, a rare autosomal dominant genetic disorder. In May 2020, the National Medical Products Administration (NMPA) in China approved the import and market launch of the drug without requiring clinical trials, after a priority review and approval process.
In the field of oncology drug development, deuterated drugs have also been continuously explored and received increasing attention. For example, the National Class 1 new drug, tosylate debrisoquine, has already completed a Phase III randomized controlled, head-to-head comparison study with the gold-standard treatment sorafenib for first-line treatment of advanced hepatocellular carcinoma. The drug met the primary endpoint and demonstrated significant survival and safety advantages, making it the first deuterated anticancer drug approved for market release globally.
Three Main Roles of Deuterium in Deuterated Drugs
As a Source of Deuterium Atoms
Deuterium gas and heavy water are the most commonly used sources of deuterium atoms in the preparation of deuterated drugs. They contain a significant amount of active deuterium atoms, which can replace the regular hydrogen atoms in drug molecules, facilitating the process of deuteration.
As Solvents or Reagents in Synthesis
In addition to serving as sources of deuterium atoms, deuterium gas and heavy water can also function as solvents or reagents in the synthesis process. This enables selective replacement of specific hydrogen atoms in the drug molecule, allowing for precise modifications to target locations or atom types.
As Analytical Tools for Research Properties
Beyond their role in synthesis, deuterium gas and heavy water can be used as analytical tools for research purposes. They aid in the exploration and validation of various properties of drug molecules, including their structure, dynamics, and metabolism.
The Effects of Deuterated Drugs
The primary function of deuterated drugs is to improve the metabolism and efficacy of a drug in the body by utilizing the rate differences between deuterium and regular hydrogen atoms in chemical reactions. Specifically, deuterated drugs can exert their effects in the following ways:
Prolonging the Drug’s Half-Life in the Body
Since deuterium is heavier than regular hydrogen, the bonds it forms with carbon atoms are stronger and harder to break by enzymes or other factors. This means that deuterated drugs can stay in the body for a longer period, making them less prone to breakdown or elimination. As a result, this can reduce the frequency and dosage of administration, improve the drug’s bioavailability and efficacy, while also lowering the risks of withdrawal symptoms and tolerance.
Reducing the Fluctuations of the Drug in the Body
Due to the greater stability of deuterium compared to regular hydrogen, the bonds formed with carbon atoms are more uniform and less susceptible to temperature, pH, solvents, and other environmental factors. This allows deuterated drugs to maintain a more stable concentration in the body, minimizing fluctuations in drug levels. This stability can reduce dosing intervals and variations, enhancing the therapeutic effect and safety of the drug, while simultaneously lowering the risks of side effects and toxicity.
Altering the Drug’s Metabolic Pathways in the Body
Because deuterium is more resistant to recognition or breakdown by enzymes and other factors, the bonds it forms with carbon atoms are less likely to participate in certain specific chemical reactions. This means that deuterated drugs can avoid or reduce undesirable or harmful metabolic pathways in the body, leading to the formation or retention of beneficial or effective metabolites. This can enhance or prolong the drug’s mechanism of action and target effects while reducing adverse reactions and drug interactions caused by metabolic products.
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