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What are Deuterated Drugs?

Deuterium (D) is a stable, non-radioactive isotope of hydrogen (H), and deuterated drugs refer to drugs containing deuterium atoms, which are obtained by replacing one or more carbon-hydrogen bonds (C-H) at specific metabolic sites on the drug molecule with carbon-deuterium bonds (C-D). Because deuterium has a larger atomic mass than hydrogen, the C-D bond is more stable than the C-H bond (6-9 times). Replacing hydrogen with deuterium in drug molecules can slow down the systemic clearance rate, prolonging the half-life of the drug in the body. This can reduce the single dose of the drug without affecting its pharmacological activity, thereby achieving the goal of reducing drug toxicity and side effects, thus enhancing the safety and tolerability of the drug and achieving better therapeutic effects.

Schematic structural formula of the deuterated drug deuterobenazine.

* Below are only some of BOC Sciences' deuterated compounds, for more please click on our Product List. Also, more custom isotope labeling services are available.

Principles of Deuterated Drugs

Hydrogen has three known isotopes:

(1) Protium: with one proton and no neutrons in the nucleus, constituting approximately 99.98% of natural hydrogen, and it is non-radioactive;

(2) Deuterium, also known as heavy hydrogen, with one proton and one neutron in the nucleus, comprising about 0.02% of natural hydrogen, and it is non-radioactive;

(3) Tritium, also known as super heavy hydrogen, with one proton and two neutrons in the nucleus, constituting about 0.004% of natural hydrogen, and it is radioactive.

Protium and deuterium are stable isotopes in nature. And research discovered that replacing hydrogen atoms at specific sites in drugs with deuterium atoms (deuteration) could potentially extend the half-life of drug metabolism. Thus, deuteration began to be applied in the fields of drug metabolism and toxicology.

The metabolic processes of drugs in the human body often involve enzymes such as cytochrome P450, monoamine oxidase, and aldehyde oxidase, catalyzing the conversion of drugs into a series of metabolites. During this process, the metabolic sites of the parent drug mainly undergo carbon-hydrogen bond cleavage, where stable carbon-hydrogen bonds become active after absorbing energy and then break. Chemical bonds formed by isotopes with greater mass have lower zero-point vibrational energy and require more energy to become active. Carbon-deuterium bonds require 341.4 kJ/mol compared to 338 kJ/mol for carbon-hydrogen bonds, making carbon-deuterium bonds more stable. Since drugs are composed of countless molecules, when several hydrogen atoms involved in drug metabolism pathways are replaced by deuterium, the reaction rate of metabolic enzymes may decrease by 6 to 10 times, and the metabolic pathways may change, resulting in fewer metabolites. Due to the similar spatial structure of carbon-deuterium and carbon-hydrogen bonds, the stereochemistry and spatial flexibility of molecules remain unchanged after deuteration, allowing deuterated compounds to retain biochemical efficacy and selectivity. In theory, deuteration may prolong the duration of drug action in the body, reduce dosage, improve efficacy, and decrease toxicity.

What are the Advantages of Deuterated Drugs?

By leveraging these properties of deuterium substitution for hydrogen, it is possible to enhance the pharmacokinetic characteristics and metabolic profile of drugs without compromising their activity, ultimately leading to reduced dosing frequency, dosage, and adverse effects. There are several advantages that can be summarized through some of the deuterated drugs that have been successfully validated.

Increased Drug Exposure

The world's first approved deuterated drug, deutetrabenazine, a deuterated compound of tetrabenazine used to treat Huntington's disease, exhibits an extended half-life from 2-8 hours to 9-10 hours post-deuteration, resulting in decreased dosing frequency and dosage with reduced adverse effects.

Decreased Formation of Specific Metabolites & Improving Metabolic Profiles

Paroxetine, an antidepressant, can form highly active carbene metabolites in vivo, increasing the risk of accumulation for drugs primarily metabolized by CYP2D6. Deuterated derivatives of paroxetine are less susceptible to oxidation by CYP2D6, significantly reducing carbene formation and alleviating potential interactions with other CYP2D6-metabolized drugs.

Reduced First-Pass Effect & Increased Oral Bioavailability

Dextromethorphan exhibits a significant hepatic first-pass effect, rapidly metabolized by CYP2D6 into its demethylated metabolite, resulting in low oral bioavailability when administered alone. AVP-786, a deuterated derivative of dextromethorphan, demonstrates a 3-5 fold reduction in metabolism by CYP2D6 in in vitro experiments, improving its oral bioavailability.

Strategies for Deuterated Drugs Development

With the maturation of deuterium labeling technology, continuous exploration of drug targets, and gradual introduction of new drugs, incorporating isotopes such as deuterium into the active ingredients of drugs has become one of the important strategies for drug development. Currently, the development strategy of deuterated drugs mainly revolves around two categories.

Fast-Follow Strategy

The Fast-Follow strategy aims to deuterate existing drugs. The development strategy for such deuterated drugs primarily involves analyzing and identifying potential drawbacks in known drugs, such as unstable drug metabolism, undesirable pharmacokinetic parameters, generation of toxic metabolites, and drug degradation. By introducing deuterium atoms, drugs are rendered more stable, thereby overcoming or improving the aforementioned drawbacks to obtain better drugs. This strategy is often used to enhance non-deuterated drugs, but not all drugs are suitable for deuteration.

First-in-class Drug Development Strategy

This strategy involves introducing deuterium atoms into new drug molecules to create entirely new chemical entities. The development strategy for such deuterated drugs primarily involves incorporating deuterium substitution as a means of drug discovery or as one of the strategies for lead compound optimization during the drug molecule screening stage. The goal is to develop first-in-class new drugs.

The deuterium generation drugs now on the market and in development are still dominated by the Fast-Follow strategy.

Examples of Approved Deuterated Drugs

Deutetrabenazine

Deutetrabenazine is the first deuterated drug to receive market approval. Tetrabenazine was approved by the FDA in 2008 for the treatment of Huntington's disease. However, tetrabenazine can lower serotonin levels, potentially worsening the condition of certain psychiatric patients and leading to depression and suicidal thoughts. This discovery prompted the FDA to issue a black box warning, restricting the use of tetrabenazine in patients with suicidal tendencies or untreated depression. Another drawback of tetrabenazine is its metabolism via carbonyl reductase to an active metabolite, which is then metabolized via CYP2D6-mediated O-demethylation to an inactive O-demethylated metabolite. This metabolic pathway results in unfavorable pharmacokinetics, often requiring increased dosing frequency to compensate. To improve dosing regimens and reduce adverse reactions, the deuterated analogue of tetrabenazine, d6-tetrabenazine, was developed, which exhibits greater resistance of the active metabolite to CYP2D6-mediated O-demethylation. Additionally, deutetrabenazine allows for a lower dosing frequency. In 2015, deutetrabenazine was approved by the FDA for the treatment of Huntington's disease (2017) and tardive dyskinesia (2018). Deutetrabenazine represents a significant milestone in the development of deuterated drugs and has established a clearer framework in this field.

* Related Products from BOC Sciences.

Donafenib

Sorafenib is a multi-kinase inhibitor approved for the treatment of unresectable or metastatic liver cancer and advanced kidney cancer. Donafenib, the deuterated counterpart of sorafenib, undergoes deuteration in the methyl structure of sorafenib's N-methylpyridine amide. Donafenib is currently used as a first-line treatment for previously untreated unresectable hepatocellular carcinoma patients, and its use as monotherapy or in combination with other drugs for treating other cancers is under evaluation. Deuterated donafenib exhibits significant statistical advantages over non-deuterated sorafenib in terms of pharmacokinetics, efficacy, and safety.

* Related Products from BOC Sciences.

Deucravacitinib

Deucravacitinib, a deuterated drug, obtained FDA approval in 2022, marking a milestone event in the history of deuterated drug development. It is the first deuterated drug designed from scratch, departing from the previous strategy of deuteration based on known drugs or candidate drugs. As a first-line therapy, deucravacitinib has demonstrated promising results in clinical trials for treating moderate to severe plaque psoriasis in adults.