Table 1.
Selected examples of deuterated compounds
| Structure | Reaction | Therapeutic indication or use (mechanism of action) | Advantage given by deuterium incorporation | Highlighted in reference |
|---|---|---|---|---|
 d9-caffeine
|
CYP1A2-mediated amide and amine N-dealkylation | Apnoea of prematurity in infants; pain medications associated with analgesic agents (adenosine receptor antagonist) | Increase in PK parameters (longer t½, higher AUC); slower oral absorption | 35–40 |
|
(d3-enzalutamide, HC-1119) |
CYP-mediated amide N-dealkylation | Castration-resistant prostate cancer (androgen receptor antagonist) | PK improvement; reduced formation of metabolites associated with side effects | 41,42 |
|
(d9-ivacaftor, CTP-656, VX-561) |
CYP3A4-mediated oxidations | Cystic fibrosis (CFTR modulator) | Increased PK parameters (longer t½ and higher exposure) | 43,168,169 |
 AVP-786 (d6-dextromethorphan and quinidine)
|
CYP2D6-mediated O-dealkylation | Agitation in Alzheimer disease (multitarget modulator) | Reduced amount of co-administered booster | 45–47 |
 Dosimertinib
|
CYP-mediated amine N-dealkylation | Non-small-cell lung cancer (EGFR inhibitor) | Reduced toxicity due to lower levels of non-selective N-demethylated metabolites | 50 |
 d1-JNJ38877605
|
AO-mediated oxidation | Cancer (ATP-competitive inhibitor of MET kinase) | Increased oral exposure and anticancer activity; reduced nephrotoxic metabolites | 5,57 |
 DRX-164 (SP-3164)
|
Enantiomerization | Haematological cancer and solid tumours (cereblon-binding molecular glue) | Reduced enantiomerization and higher efficacy | 58,60 |
|
(d1-(R)-pioglitazone) |
Enantiomerization | X-linked adrenoleukodystrophy and nonalcoholic steatohepatitis (MPC inhibitor) | Reduced side effects associated with off-target agonism on PPARγ | 61,62 |
 Y180
|
Epimerization | COVID-19 (Mpro inhibitor) | Reduced epimerization in vivo | 63,64 |
 RT001
|
ROS-driven oxidation | Neurodegenerative diseases (reduction of oxidative stress) | Increased resistance to oxidative damage | 68–70 |
 Heroin vaccine
|
– | Opioid dependence | Enhanced immune response | 73 |
|
(d6-tetrabenazine) |
O-dealkylation | Huntington chorea and tardive dyskinesia (VMAT2 inhibitor) | Increased exposure to active metabolites | 6,75,77–93 |
 Donafenib (d3-sorafenib)
|
– | Hepatocellular carcinoma and other advanced solid tumours (multi-kinase inhibitor) | Higher drug absorption and exposure at steady state; longer median overall survival; lower incidence of adverse effects | 7,95–99 |
 VV116 (JT001)
|
Oxidation and ring opening | COVID-19 and RSV (viral RNA-dependent RNA polymerase inhibitor) | Contribution to the switch from intravenous to oral administration | 8,103–105 |
|
(BMS-986165) |
Amide N-dealkylation | Psoriasis and other autoimmune diseases (JH2 TYK2 inhibitor) | Avoiding the formation of non-selective metabolites | 9,115,117,118,120–127,129,130,170,171 |
|
(d8-ruxolitinib, CTP-543) |
CYP-mediated oxidation | Alopecia areata (JAK1/JAK2 inhibitor) | Increased exposure and t½ | 132 |
|
(PHA-022121) |
– | Hereditary angioedema (bradykinin B2 receptor antagonist) | Decreased intrinsic clearance in microsomes | 11,134 |
 VX-984 (M9831)
|
AO-mediated oxidation | Advanced solid tumours (ATP-competitive inhibitor of the catalytic subunit of DNA-dependent protein kinase) | – | 12,135,172 |
Deutenzalutamide
Deutivacaftor
PXL065
Deutetrabenazine
Deucravacitinib
Deuruxolitinib
DeucrictibantCompounds are presented in the order of their discussion in the article. AO, aldehyde oxidase; AUC, area under the curve; CFTR, cystic fibrosis transmembrane protein regulator; COVID-19, coronavirus disease 2019; CYP, cytochrome P450; JAK, Janus kinase; JH2, JAK homology 2; Mpro, main protease; PK, pharmacokinetic; PPARγ, peroxisome proliferator-activated receptor-γ; ROS, reactive oxygen species; RSV, respiratory syncytial virus; t½, half-life; TYK2, tyrosine kinase 2; VMAT2, vesicular monoamine transporter 2.