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Purpose <p>The catabolism of leuprorelin was studied in rat-derived hepatic and extrahepatic in vitro models and in vivo to compare the catabolism with human models and to evaluate whether the earlier reported NADPH-dependency of leuprorelin catabolism affects in vivo correlation. Furthermore, the mechanism of NADPH-dependency was investigated with human and rat-derived models.</p> Methods <p>Leuprorelin was incubated with rat hepatic and extrahepatic in vitro models. Additionally, leuprorelin was dosed into rats to determine what in vitro system provided the best correlation with in vivo. Lastly, leuprorelin was incubated with rat and human derived enzyme sources to identify the processes responsible for NADPH-dependent catabolism. The analysis was performed with UPLC-HRMS.</p> Results <p>The same NADPH-dependency of leuprorelin catabolism as in human was observed with rat liver and kidney S9 fraction. Furthermore, the best in vitro – in vivo correlation was provided by the incubation with kidney S9 fraction in the absence of NADPH. The catabolite profiles produced in the incubations with the employed rat and human sub-cellular fractions supplemented with NADPH were replicable with the addition of DTT in the incubations. Therefore, the NADPH-dependency was not caused by metabolic enzymes, but rather by processes maintaining the reductive potential of the cell, activating peptidases responsible for the catabolism of leuprorelin.</p> Conclusion <p>The influence of DTT on the peptidase activity has been known, but the NADPH-dependency of the therapeutic peptide catabolism is novel, and more research is needed to assess the importance of this effect on in vitro – in vivo correlation for other therapeutic peptides.</p>

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In Vitro and In Vivo Catabolite Profiles of Leuprorelin in Rat and the Effects of NADPH in Leuprorelin Catabolism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月7日

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  • Juha Jyrkäs,
  • Toni Lassila,
  • Janne Mannila,
  • Ari Tolonen

摘要

Purpose

The catabolism of leuprorelin was studied in rat-derived hepatic and extrahepatic in vitro models and in vivo to compare the catabolism with human models and to evaluate whether the earlier reported NADPH-dependency of leuprorelin catabolism affects in vivo correlation. Furthermore, the mechanism of NADPH-dependency was investigated with human and rat-derived models.

Methods

Leuprorelin was incubated with rat hepatic and extrahepatic in vitro models. Additionally, leuprorelin was dosed into rats to determine what in vitro system provided the best correlation with in vivo. Lastly, leuprorelin was incubated with rat and human derived enzyme sources to identify the processes responsible for NADPH-dependent catabolism. The analysis was performed with UPLC-HRMS.

Results

The same NADPH-dependency of leuprorelin catabolism as in human was observed with rat liver and kidney S9 fraction. Furthermore, the best in vitro – in vivo correlation was provided by the incubation with kidney S9 fraction in the absence of NADPH. The catabolite profiles produced in the incubations with the employed rat and human sub-cellular fractions supplemented with NADPH were replicable with the addition of DTT in the incubations. Therefore, the NADPH-dependency was not caused by metabolic enzymes, but rather by processes maintaining the reductive potential of the cell, activating peptidases responsible for the catabolism of leuprorelin.

Conclusion

The influence of DTT on the peptidase activity has been known, but the NADPH-dependency of the therapeutic peptide catabolism is novel, and more research is needed to assess the importance of this effect on in vitro – in vivo correlation for other therapeutic peptides.