Pharmacokinetics, Toxicity, The Effects On Free Radicals And Drug Metabolizing Enzymes Of Ceftiofur Sodium Liposomes

Liposome is a microscopic spherical particle can encapsulate drug in the lipid bilayer and has long-term and sustained-release effect. Ceftiofur sodium is a third generation broad spectrum cephalosporin widely used clinically to treat respiratory diseases and mastitis in livestock via intramuscular (i.m.) injection. Ceftiofur sodium liposome is the suspension formed by a lipid bilayer enclosing ceftiofur sodium. Five relative experiments were designed here to evaluate the clinical pharmacological characteristics of ceftiofur sidium liposomes, as to provide guidance and theoretical basis for the use of ceftiofur sodium liposomes in clinical veterinary.1. In vitro release of ceftiofur sodium liposomesIn vitro release of ceftiofur sodium liposomes was deteced by dynamic dialysis method which use PBS buffer (pH6.5) as the release medium. The results showed that the fraction release of ceftiofur sodium liposomes at24h is56.48%, and ceftiofur sodium is90%at2h,94.68%after24h. Ceftiofur sodium liposome has significant long-term and sustained-release effect compared with the non-encapsulated ceftiofur sodium.2. pharmacokinetics of ceftiofur sodium liposomes in cowsTo examine the metabolism and pharmacokinetic parameters of ceftiofur sodium liposomes, six healthy, adult cows in two treatment groups were dosed intravenously with ceftiofur sodium liposomes and ceftiofur sodium, serial blood samples collected, and plasma concentrations determined by high performance liquid chromatography. The results showed that ceftiofur sodium liposome was still detectable after48h, indicating that ceftiofur sodium liposome has long-term effect. Intravenous plasma concentration profiles of liposomes best fit a two compartment model and the elimination half-life was2.11times that of ceftiofur sodium. Thus, this liposome preparation provided therapeutically effective plasma concentrations for a longer duration than with the drug alone, making it more effective and convenient for use in treating bovine mastitis that requires long duration maintenance of therapeutic plasma concentrations.3. The toxicity of ceftiofur sodium liposomes15mice were given ceftiofur sodium liposomes at dose of1000mg/kg,500mg/kg and200mg/kg by intraperitoneal injection, all the mice were still alive after7days of administration.56healthy SPF mice were divided into7groups randomly, were injected20,10.5times the clinical dose of ceftiofur sodium and ceftiofur sodium liposomes, one group were given physiological saline as the control. Blood routine examination, biochemical analysis and histopathological were tested after21days continuous injection. The results showed that T-tests of mice blood routine and biochemical data revealed that high dose group of ceftiofur sodium has obvious toxicity to mice. Though the low dose group of ceftiofur sodium liposomes has some toxicity to mice, the toxicity was smaller than the same dose of ceftiofur sodium. The pathology sections of liver and kidney showed that the toxicity of ceftiofur sodium liposomes to mice was significantly smaller than ceftiofur sodium. Conclusion:The liposomes which encapsulated ceftiofur sodium can decreased toxicity, increased security.4. Effects of ceftiofur sodium liposomes on free radical formation in miceTo examine the effects of ceftiofur sodium liposomes on the free radical formation in liver of mice,24mice were assigned randomly into three groups, i.e.,1) ceftiofur sodium;2) ceftiofur sodium liposomes and3) physiological saline. Treatments were applied via intraperitoneal injections for7days. At the end of the treatment period, animals were euthanized and liver collected for analysis of superoxide dismutase (SOD) activity and malondialdehyde (MDA) contents and the ability of liver tissue to suppress hydroxyl radical formation. The results showed that gender had no significant effect on free radical formation. Ceftifur sodium liposomes-treated mice had higher activity of SOD (85.40±2.59)than ceftiofur sodium-treated(75.42±3.29) mice; however, MDA content and the ability of liver tissue to suppress hydroxyl radical formation did not reach statistical significance among groups. It was concluded that ceftiofur sodium liposomes can improve the SOD activity and reduce the cell toxicity brought by free radical compared to ceftiofur alone in mice.5. Effects of ceftiofur sodium liposomes on drug metabolizing enzymeTo understand the effects of ceftiofur sodium liposomes on liver microsomal drug metabolizing enzyme,24Kunming mice were randomly divided into three groups, intraperitoneal injection2.2mg/kg ceftiofur sodium liposomes and ceftiofur sodium respectively for7days, another group as the control. Mice were euthanized after completion of the injection, liver was collected to prepare liver microsomes and protein concentration, content of cytochrome b5, activities of NADPH-cytochrome C reductase, aminopyrine-N-demethylase enzyme, erythromycin-N-demethylase and aniline hydroxylase were detected in this study. The results revealed that ceftiofur sodium liposomes showed inhibition effect on these five drug metabolizing enzymes, the inhibition effect of ceftiofur sodium liposomes on NADPH-cytochrome C reductase was significantly lower than control group, the rest are no significant differences. The activities of these five enzymes are very low, this low activity well explained the slower metabolic rate of ceftiofur sodium liposomes, thus avoiding the cytotoxic brought by higher drug peak concentration.