Strain and interindividual differences in lamotrigine‐induced liver injury in mice

Abstract

Lamotrigine (LTG) has been widely prescribed as an antipsychotic drug, although it causes idiosyncratic drug‐induced liver injury in humans. LTG is mainly metabolized by UDP‐glucuronosyltransferase, while LTG undergoes bioactivation by cytochrome P450 to a reactive metabolite; it is subsequently conjugated with glutathione, suggesting that reactive metabolite would be one of the causes for LTG‐induced liver injury. However, there is little information regarding the mechanism of LTG‐induced liver injury in both humans and rodents. In this study, we established an LTG‐induced liver injury mouse model through co‐administration with LTG and a glutathione synthesis inhibitor, l‐buthionine‐(S,R)‐sulfoximine. We found an increase in alanine aminotransferase (ALT) levels (>10 000 U/L) in C57BL/6J mice, with apparent interindividual differences. On the other hand, a drastic increase in ALT was not noted in BALB/c mice, suggesting that the initiation mechanism would be different between the two strains. To examine the cause of interindividual differences, C57BL/6J mice that were co‐administered LTG and l‐buthionine‐(S,R)‐sulfoximine were categorized into three groups based on ALT values: no‐responder (ALT <100 U/L), low‐responder (100 U/L < ALT < 1000 U/L) and high‐responder (ALT >1000 U/L). In the high‐responder group, induction of hepatic oxidative stress, inflammation and damage‐associated molecular pattern molecules in mRNA was associated with vacuolation and karyorrhexis in hepatocytes. In conclusion, we demonstrated that LTG showed apparent strain and interindividual differences in liver injuries from the aspects of initiation and exacerbation mechanisms. These results would support interpretation of the mechanism of LTG‐induced liver injury observed in humans.

TRAIL Coated Genetically Engineered Immunotherapeutic Nano‐Ghosts Vesicles Target Human Melanoma‐Avoiding the Need for High Effective Therapeutic Concentration of TRAIL

“…In the immunogenicity studies, alanine transaminase (ALT) measurement of serum samples taken from tumor-bearing SCID mice treated with GE-iNGs and free sTRAIL showed ALT levels that are normally obtained for a non-toxic drug (<40 U mL −1 ; Figure 7A). [52,53] H&E staining from liver samples taken from mice treated with GE-iNGs or sTRAIL showed no apparent toxicity compared to untreated SCID mice (Figure 7B). In addition, the inflammatory cytokines TNF-α, INF-γ, IL1-β, and IL-6 levels did not rise in C57/BL mice treated with GE-iNGs up to 3 weeks post injection compared to untreated mice (Figure 7C).…”

The development of the Metabolic-associated Fatty Liver Disease during pharmacotherapy of mental disorders - a review

“…Lamotrigine (LTG) Among the others commonly used antiepileptic drugs as MS, the use of LTG seems to be the safest in the context of the risk of the development of NAFLD, as it leads to a lower degree of weight gain and lipid metabolism disorders [54,82]. Also, as in the case of CBZ, the use of LTG is associated with the risk of hepatotoxicity and the development of DILI through idiosyncrasy [86,87].…”

“…Lamotrygina (Lamotrigine, LTG) Spośród wszystkich leków przeciwpadaczkowych stosowanych jako MS, LTG wydaje się być najbezpieczniejsza w kontekście ryzyka rozwoju NAFLD, ponieważ prowadzi do mniejszego stopnia przyrostu masy ciała i zaburzeń gospodarki lipidowej [54,82]. Również, jak w przypadku CBZ, stosowanie LTG wiąże się z ryzykiem hepatotoksyczności i rozwojem DILI na drodze idiosynkrazji [86,87].…”