Deuterated drugs are medicinal products where one or more hydrogen atoms within the drug molecule have been replaced by deuterium. Deuterium, also known as “heavy hydrogen,” is a stable isotope of hydrogen with an extra neutron, making it heavier than regular hydrogen (protium). This modification can significantly influence how a drug behaves inside the body.
This approach of modifying existing drugs using deuterium is an example of bioisosterism, a strategy in drug discovery where similar biological effects are achieved by substituting one part of a molecule with another. While the concept of using deuterium in drug development dates back to the 1970s, it has only recently seen significant approvals and gained broader attention in the pharmaceutical industry.
The Role of Deuterium in Drug Metabolism
Deuterium is an isotope of hydrogen, containing an extra neutron compared to common hydrogen (protium). This makes deuterium approximately twice as heavy, a difference that profoundly affects chemical bonds.
When deuterium replaces hydrogen in a drug molecule, it forms a carbon-deuterium (C-D) bond instead of a carbon-hydrogen (C-H) bond. The C-D bond is stronger and more stable than the C-H bond, influencing how enzymes interact with the drug during metabolism.
Many metabolic processes, especially those involving cytochrome P450 (CYP450) enzymes, break C-H bonds to break down drugs. Since the C-D bond is more resistant to cleavage, its presence slows down drug metabolism. This kinetic isotope effect means the drug remains active longer, extending its half-life and improving stability.
Clinical Advantages of Deuterated Drugs
The altered metabolism from deuterium substitution offers several benefits for patients and drug development. One advantage is improved pharmacokinetics. By slowing drug breakdown, deuteration leads to a longer duration of action, which can reduce dosing frequency and improve treatment adherence.
Another advantage relates to side effects and safety. When drugs are metabolized, they often produce various metabolites, some of which can be inactive or toxic. Strategically placing deuterium atoms can alter a drug’s metabolic pathway, reducing the formation of undesirable metabolites. This leads to fewer or less severe side effects and an improved safety profile.
Deuteration can also lead to increased efficacy at lower doses. Since the drug remains in the body longer and its breakdown is slowed, a smaller amount of the deuterated drug might achieve the same therapeutic effect. This contributes to a better tolerability profile. Additionally, deuteration can enhance oral bioavailability, allowing for more efficient absorption.
Approved Deuterated Drugs and Their Impact
Several deuterated drugs have received regulatory approval or are in advanced clinical development, demonstrating the real-world application of this technology. Deutetrabenazine (Austedo) was the first deuterated drug approved by the U.S. Food and Drug Administration (FDA) in 2017. It treats chorea associated with Huntington’s disease and tardive dyskinesia.
Deutetrabenazine is a deuterated version of tetrabenazine. Deuteration of its methoxy groups makes them more resistant to enzymatic breakdown, slowing the metabolism of active metabolites. This leads to a longer half-life and less patient-to-patient variability, allowing for reduced dosage and longer dosing intervals compared to the non-deuterated form.
Another approved deuterated drug is Deucravacitinib, which received FDA approval in 2022 for plaque psoriasis. This drug is a deuterated JAK (Janus kinase) inhibitor targeting TYK2. Deuteration in deucravacitinib helps maintain selectivity by preventing non-selective metabolite formation, improving its therapeutic profile for autoimmune diseases. Donafenib, approved in China in 2021 for unresectable hepatocellular carcinoma, is a deuterated form of sorafenib, showing improved pharmacokinetic properties, greater efficacy, and fewer adverse effects.