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 2 h. 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.

Chronopharmacology and Antimicrobial Therapeutics

“…Diurnal rhythm of PEPT1 [119,121], the intestinal peptide transporter involved in the absorption of some beta-lactam antibiotics orally administered, is probably related to the greater C max and faster t max and initial absorption rate observed for ceftibuten after its administration to rats during the activity phase, when compared with those pharmacokinetic parameters calculated after the rest phase [194]. Higher biliary excretion of ampicillin [187,188,190] was determined during the active phase. This dosing time-dependent variation may proceed from the previously reported circadian rhythm on basal bile flow and biliary anion carrier system [190,221].…”

“…In contrast, daily variations have been proved for both kinetic disposition [142,[187][188][189][190][191][192][193][194][195][196][197] and toxicity [191,[198][199][200][201][202][203][204][205][206][207][208][209][210][211][212] of some antimicrobial drugs.…”

Circadian Rhythms in Infectious Diseases: Do They Matter?

“…Table 1 also shows that the maximal serum clearance of gentamicin (17,23), tobra mycin (24) and amikacin (25) was found when these antibiotics were injected in the middle of the activity period of rodents. In the cases of ampicillin (26) and liposomal ampicillin (27), maximal clearance was reported to occur during the activity period of animals. In agreement with these data , the area under the serum (17,23), tobramycin (24) and amikacin (25) were injected in the middle of the resting period .…”