PMID- 38047363
OWN - NLM
STAT- Publisher
LR  - 20240112
IS  - 2949-6829 (Electronic)
IS  - 2949-6810 (Linking)
DP  - 2023 Dec 1
TI  - Species-specific Bioactivation of Morpholines as a Causative of Drug Induced 
      Liver Injury Observed in Monkeys.
LID - 10.2174/0118723128260455231104180653 [doi]
AB  - BACKGROUND: Everolimus, an allosteric mechanistic target of rapamycin (mTOR) 
      inhibitor, recently demonstrated the therapeutic value of mTOR inhibitors for 
      Central Nervous System (CNS) indications driven by hyperactivation of mTOR. A 
      newer, potent brain-penetrant analog of everolimus, referred to as (1) in this 
      manuscript 
      [(S)-3-methyl-4-(7-((R)-3-methylmorpholino)-2-(thiazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)morpholine,(1)] 
      catalytically inhibits mTOR function in the brain and increases the lifespan of 
      mice with neuronal mTOR hyperactivation. INTRODUCTION: Early evaluation of the 
      safety of 1 was conducted in cynomolgus monkeys in which oral doses were 
      administered to three animals in a rising-dose fashion (from 2 to 30 mg/kg/day). 
      1 produced severe toxicity including the evidence of hepatic toxicity, along with 
      non-dose proportional increases in drug exposure. Investigations of cross-species 
      hepatic bioactivation of 1 were conducted to assess whether the formation of 
      reactive drug metabolites was associated with the mechanism of liver toxicity. 
      METHOD: 1 contained two morpholine rings known as structural alerts and can 
      potentially form reactive intermediates through oxidative metabolism. 
      Bioactivation of 1 was investigated in rat, human and monkey liver microsomes 
      fortified with trapping agents such as methoxylamine or potassium cyanide. 
      RESULTS: Our results suggest that bioactivation of the morpholine moieties to 
      reactive intermediates may have been involved in the mechanism of liver toxicity 
      observed with 1. Aldehyde intermediates trappable by methoxylamine were 
      identified in rat and monkey liver microsomal studies. In addition, a total of 
      four cyano conjugates arising from the formation of iminium ion intermediates 
      were observed and identified. These findings may potentially explain the observed 
      monkey toxicity. Interestingly, methoxylamine or cyano adducts of 1 were not 
      observed in human liver microsomes. CONCLUSION: The bioactivation of 1 appears to 
      be species-specific. Circumstantial evidence for the toxicity derived from 1 
      point to the formation of iminium ion intermediates trappable by cyanide in 
      monkey liver microsomes. The cyano conjugates were only observed in monkey liver 
      microsomes, potentially pointing to cause at least the hepatotoxicity observed in 
      monkeys. In contrast, methoxylamine conjugates were detected in both rat and 
      monkey liver microsomes, with only a trace amount in human liver microsomes. 
      Cyano conjugates were not observed in human liver microsomes, challenging the 
      team on the drugability and progressivity of 1 through drug development. The 
      mechanisms for drug-induced liver toxicity are multifactorial. These results are 
      highly suggestive that the iminium ion may be an important component in the 
      mechanism of liver toxicity 1 observed in the monkey.
CI  - Copyright(c) Bentham Science Publishers; For any queries, please email at 
      epub@benthamscience.net.
FAU - Gunduz, Mithat
AU  - Gunduz M
AUID- ORCID: 0009-0002-1495-1408
AD  - Department of Pharmacokinetic Sciences, Global Biotransformation, Novartis 
      Biomedical Research, Inc., Cambridge, MA, US
FAU - Argikar, Upendra A
AU  - Argikar UA
AUID- ORCID: 0009-0002-1495-1408
AD  - Department of Pharmacokinetic Sciences, Global Biotransformation, Novartis 
      Biomedical Research, Inc., Cambridge, MA, US
AD  - Bill & Melinda Gates Medical Research Institute, Cambridge, MA, US
FAU - Cirello, Amanda L
AU  - Cirello AL
AD  - Department of Pharmacokinetic Sciences, Global Biotransformation, Novartis 
      Biomedical Research, Inc., Cambridge, MA, US
FAU - Brown, Alan P
AU  - Brown AP
AD  - Department of Preclinical Safety, Novartis Biomedical Research, Inc., 
      Translational Medicine, Cambridge, MA, US
FAU - Bonazzi, Simone
AU  - Bonazzi S
AD  - Department of Global Discovery Chemistry, Novartis BioMedical Research, Inc., 
      Cambridge, MA, US
FAU - Walles, Markus
AU  - Walles M
AD  - Department of Pharmacokinetic Sciences, Global Biotransformation, Novartis 
      Biomedical Research, Inc., Basel, Switzerland
LA  - eng
PT  - Journal Article
DEP - 20231201
PL  - United Arab Emirates
TA  - Drug Metab Bioanal Lett
JT  - Drug metabolism and bioanalysis letters
JID - 9918418288306676
SB  - IM
OTO - NOTNLM
OT  - Potassium cyanide
OT  - aldehyde intermediate
OT  - bioactivation
OT  - iminium ion intermediate
OT  - liver microsomes
OT  - methoxylamine
OT  - morpholine
EDAT- 2023/12/04 06:42
MHDA- 2023/12/04 06:42
CRDT- 2023/12/04 05:26
PHST- 2023/05/02 00:00 [received]
PHST- 2023/09/25 00:00 [revised]
PHST- 2023/10/03 00:00 [accepted]
PHST- 2023/12/04 06:42 [medline]
PHST- 2023/12/04 06:42 [pubmed]
PHST- 2023/12/04 05:26 [entrez]
AID - DMBL-EPUB-136463 [pii]
AID - 10.2174/0118723128260455231104180653 [doi]
PST - aheadofprint
SO  - Drug Metab Bioanal Lett. 2023 Dec 1. doi: 10.2174/0118723128260455231104180653.