09 October 2024

Deuterated Nefazodone For the Treatment of Antidepression

Nefazodone is an antidepressant medication marketed by Bristol-Myers Squibb. It was primarily prescribed to treat major depressive disorder. Although it is structurally similar to trazodone, nefazodone has a mechanism of action different from other antidepressants and, hence, lacks the risk for major cardiovascular toxicity seen with tricyclics and insomnia and inhibition of REM sleep seen with the selective serotonin reuptake inhibitors 1 .

Its sale was discontinued in 2003 in some countries, due to the possibility of hepatic (liver) injury. Drug-induced hepatic injuries were associated with a risk of elevated need for a liver transplant, or even death, with the incidence of severe liver damage was shown to be approximately 1 in 250,000 to 300,000 patient-years 1,2

The Food and Drug Administration (FDA) has determined that SERZONE (nefazodone hydrochloride (HCl)) was not withdrawn from sale for reasons of safety or effectiveness. This determination means that FDA will not begin procedures to suspend approval of abbreviated new drug applications (ANDAs) for nefazodone HCl, and FDA may continue to approve ANDAs for nefazodone HCl 3 .

In August 2020, Teva Pharmaceuticals placed nefazodone in shortage due to a shortage of a raw ingredient. On December 20, 2021, nefazodone was again made available in all strengths. 4 it continues to be available in the United States in generic from one manufacturer, Teva Pharmaceuticals.

Mechanism of Action

Within the serotonergic system, nefazodone acts as an antagonist at type 2 serotonin (5-HT2) post-synaptic receptors and inhibits pre-synaptic serotonin (5-HT) reuptake. These mechanisms increase the amount of serotonin available to interact with 5-HT receptors.

Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally. Nefazodone also antagonizes alpha (1)-adrenergic receptors, a property which may be associated with postural hypotension. In vitro binding studies showed that Nefazodone's affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, and beta or alpha (2)- adrenergic receptors is not significant.

Toxicity

Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone. Hepatotoxicity may be mediated by toxic intermediates of its metabolism. Literature suggests that 2- chloro-1,4-benzoquinone and quinone- imine (metabolite 3) may contribute to the etiology of nefazodone hepatotoxicity. It is reasonable to expect that the reactive quinone-imine or p-benzoquinone intermediate will form covalent adducts to hepatic proteins, with potentially deleterious consequences 8 . That the potency of P450 3A4 inhibition by nefazodone significantly increases with time certainly provides preliminary evidence for covalent adduct formation with the enzyme that results in its inactivation.

Strategy to mitigate toxicity

Literature evidences showed that the hydrogen (H) replacement with deuterium (D) (a naturally occurring isotope of hydrogen) offers a more stable bond with carbon (C-D) as compared to bond of carbon with hydrogen (C-H). The increased C-D bond strength usually results in increased metabolic stability of the molecule and extended metabolic half-life of the drug. This unique feature makes it difficult to break C-D bond and hence slower rate of reaction compared to C-H bond and more stable towards the enzymatic cleavage (CYP450) in in-vivo system

Deuteration at the soft spot in Nefazodone helped to reduce the formation of reactive metabolite and further reduced the possibility of hepatotoxicity. Further reduction in metabolism of the parent compound will reduce daily dose related toxicity. Deuterated analog of Nefazodone was tested in Human liver microsome (HLM). The objective of this study was to compare metabolism of Nefazodone and Deuterated Nefazodone, especially formation of the hydroxychloro-derivative m-Chlorophenyl piperazine considered as a toxic intermediate. 9

Conclusions

Formation of hydroxylated and dealkylated metabolites from Nefazodone and Deuterated - Nefazodone after incubation with human liver microsome and NADPH was studies using LC-MS/MS method.
In in vitro incubations, both Nefazodone and Deuterated-Nefazodone were rapidly metabolized (Clint in vitro >150µL/min/mg protein)
In metabolite identification assays, rapid formation of OH-Nefazodone and m- Chlorophenyl piperazine from Nefazodone was observed. In case of Deuterated-Nefazodone, both hydroxylated and dealkylated (Deuterated-m- Chlorophenyl piperazine) formation occurred. Metabolite formation was found to reach maximum levels by about 10 min under the experimental conditions employed. The metabolites were further characterized by MRM method to observe specific fragments.
Comparison of formation of OH- and m-Chlorophenyl piperazine metabolites based on response in LC-MS/MS showed that Deuterated-Nefazodone generated notably less levels of both metabolites (50-60% lower in Deuterated-Nefazodone).
Further rigorous quantitative assessment of reduced generation of Deuterated-m-Chlorophenyl piperazine from Deuterated-Nefazodone using reference standards for reactive metabolites is needed to validate the findings of this report.

Reference

WHO Pharmaceuticals Newsletter No. 1, 2003.
Safety data and withdrawal of hepatotoxic drugs". Therapie. 76 (6): 715–723.
Federal Register / Vol. 69, No. 206 / Tuesday, October 26, 2004 / Notices
www.tevausa.com. Retrieved 2022-01-23.
Adverse effect of nefazodone: hepatitis". Med J Aust. 170 (9): 452,1999.
www.thepharmaletter.com
Drug Patent Watch. Retrieved 3 June 2017.
DRUG METABOLISM AND DISPOSITION; 33:243–253, 2005
Patent No 444456, Clearsynth Lab