Pharmacokinetics Of The Novel Peptide Deformylase Inhibitors In Rats

In recent years, the treatment for infectious diseases and the development of new therapeutic agents for these diseases have confronted a huge challenge due to the occurrence of pathogenic microorganisms resistance and cross resistance. Studies have identified that peptide deformylase (PDF), which widely exists in prokaryotesis, is one of key enzymes in bacteria protein synthesis and could be served as a unique new antibiotics target. The mechanisms of action for many compounds targeting PDF have been clearly understood. Among them, LBM-415 is typically representative as a new type of PDF inhibitors. LBM-415 was initially developed by the Vi-curon Pharmaceuticals in America and undergone phase I clinical trial in November 2003. The Novartis Company was authorized to forecast that LBM-415 would be registered to public in 2008. LBM-415 has significant antibacterial activities to G+ bacteria G-bacteria in pre-clinical and clinical research trials.SW1204 and SW2201 were synthesized based on the core structure of LBM-415. They belong to two series of SW compounds either with the alkyl side chain or the benzene side chain in their structures. Both in vitro and in vivo efficacy studies showed that they have antimicrobial activity to staphylococcus aureus MRSA and MSSA. In this study, we investigated into the pharmacokinetic properties and bioavailability of these two compounds with the aims of providing in vivo information in terms of the absorption, distribution, metabolism and clearance and of gaining insights into the understanding of the "structure-activity relationship" of the novel PDF inhibitors. Meanwhile, we also preliminarily investigated the acute toxicity of the compounds in mouse, which might be useful for further optimization of the structures of the SW compounds.1 Pharmacokinetics and bioavailability of SW1204 The pharmacokinetic parameters of SW1204 in plasma of the rats were determined using liquid chromatography-mass spectrometry, The results showed that, after a single dose of 25 mg/kg orally, AUC(0-∞) was (34.60±4.11) mg min L, Cmax was (0.46±0.03) mg/L, t1/2was (43.22±6.50) min,tmax was (22.67±7.26) min, CL was (0.74±0.09) L/min/kg, Vd was (47.30±11.84) L/kg, and MRT (0-∞) was (70.94±4.94) min. The Cmax/MIC ratio was (3.68±0.03), suggesting that, under the given dosage, the concentration of SW1204 in the blood was too low to achieve sufficient antibacterial efficacy. To determine the bioavailability in the rats, the compound was also given by intravenous injection (5mg/kg), and the plasma AUC (0-∞) was found to be (111.56±20.49) mg min/L. The absolute bioavailability of the compound was then calculated to be 6.2%, much lower than that of LBM415.2 Pharmacokinetics and bioavailability of SW2201Similar to that for SW1204, the PK parameters for SW2201 in plasma of the rats with a dose of 25mg/kg orally were determined. The results were:AUC (0-∞) (177.73±12.81) mg min/L, Cmax (1.39±0.05) mg/L, t1/2 (54.46±15.03) min, tmax (15.00±0.00) min, CL (0.14±9.8489e-3) L/min/kg, Vd (10.76±2.15) L/kg, and MRT (0-∞) (94.34±14.90) min. The Cmax/MIC ratio was (23.17±0.83), suggesting that, under the given dosage, the concentration of SW2201 in the blood was well-maintained to achieve sufficient antibacterial efficacy. To determine the bioavailability in the rats, the compound was also given by intravenous injection (5mg/kg), and the plasma AUC (0-∞,) was found to be (100.28±16.95) mg min/L. The absolute bioavailability of the compound was then calculated to be 36.69%, much higher than that of LBM415 and SW1204, respectively.3 Preliminary observation of acute toxicity test with SW2201After a single dose (100mg/kg) intravenously to the mice, the acute toxicity of SW2201was observed for 14 days in terms of the body weight, mental state, hair color, locomotor activities, breathing, diet, urination and defecation, nose and mouth secretions and other general conditions. No obvious toxic effects of the compound were observed. A further acute toxicity experiment using a dose of 250mg/kg intravenously was conducted in the mice. While 3 mice were found to be died with unknown reason no other toxic side effect of the compound was evident in the remaining mice, indicating that LD50 for SW2201 was much higher than 250mg/kg.