Chronokinetics of Liposomal Encapsulated Ampicillin in Fasting and Nonfasting Rats

Abstract

The chronobiological effect on the pharmacokinetics of liposomal encapsulated ampicillin (LEA) was compared at noon (1200) and midnight (2400) after intravenous injection of 50 mg/kg of LEA in rats. The effects of fasting on the circadian rhythms of LEA were also investigated. Serial blood samples were collected for 2h. Bile and urine were collected during the entire study. Plasma data was analyzed by noncompartmental methods. Dosing of LEA at 2400, when the animals were active, resulted in a 50% decrease in mean residence time (MRT) and a 20% increase in systemic clearance (Cltotal). The increase in Cltotal was reflected by increases in biliary (Clbile) and renal (Clrenal) clearance at 2400. In addition, the steady-state volume of distribution (Vss) at 2400 was also decreased by about 50% as compared to dosing at 1200. Interestingly, no difference in the pharmacokinetic parameters were observed in fasting animals at 1200 and 2400. Since rats consume very little food during their sleep cycle, restriction of food intake did not have any affect on the pharmacokinetics of LEA at 1200. However, fasting rats had an approximately 36% decrease in Cltotal as compared to nonfasting rats at 2400. This decrease in systemic clearance was paralleled by a 60% and 24% decrease in Clbile and Clrenal, respectively. These variations could be attributed to changes in bile composition and/ or lipoprotein concentrations in the plasma as a result of “forced” fasting at 2400 when the animals are generally more active and food intake is high.