Plasma methionine depletion and pharmacokinetic properties in mice of methionine γ-lyase from Citrobacter freundii, Clostridium tetani and Clostridium sporogenes

PK studies were carried out after a single i.v. administration of 500 and 1000 U/kg by measuring of MGL activity in plasma samples. L-methionine concentration was measured by mass spectrometry. After single i.v. injection of 500 U/kg the circulating T1/2 of enzymes in mice varies from 73 to 123 min. The AUC0-tinf values determined for MGL 500 U/kg from C. freundii, C. tetani and C. sporogenes are 8.21 ± 0.28, 9.04 ± 0.33 and 13.88 ± 0.39 U/(ml × h), respectively. Comparison of PK parameters of three MGL sources in the dose of 500 U/kg indicated the MGL C. sporogenes to have better PK parameters: clearance 0.83(95%CI: 0.779–0.871) – was lower than C. tetanii 1.27(95%CI: 1.18–1.36) and C. freundii 1.39(95%CI: 1.30–1.49). Mice plasma methionine decreased to undetectable level 10 min after MGL 1000 U/kg injection. After MGL C. sporogenes 500 U/kg injection plasma methionine level completely omitted after 10 min till 6 h, assuming the sustainability of negligible levels of methionine ( < 5 μM) in plasma of mice for about 6 h. The recovery of methionine concentration showed the advantageous efficiency of MGL from C. sporogenes: 95% 0.010–0.022 vs 0.023–0.061 for MGL C. freundii and 0.036–0.056 for MGL C. tetani. There are no significant differences between methionine cleavage after MGL C. tetani and MGL C. sporogenes i.v. injection at all doses. MGL from C. sporogenes may be considered as promising enzyme for further investigation as potential anticancer agent. © 2017 Elsevier Masson SAS