Pharmacokinetics and bioavailability of oral cephalosporins, KR-984055 and its prodrugs, KR-999001 and KR-999002, in the rat

Abstract

KR-984055 is a new oral cephalosporin antibiotic with activity against both gram-positive and gram-negative bacteria. Lipophilic ester-type prodrugs of KR-984055, i.e., KR-999001 and KR-999002, have been synthesized in an attempt to increase the oral bioavailability of this broadspectrum antibiotic agent. In this study we determined the oral bioavailability of KR-984055 and its prodrugs in the rat, and evaluated the pharmacokinetic model that best describes the plasma concentration behavior following single intravenous (IV) and oral single dose. In addition, concentrations in plasma as well as biliary and urinary recovery of KR-984055 were determined. Also, protein binding of KR-984055 in plasma was examined in vitro. The degree of protein binding of KR-984055 was in the range of 92.09-94.77%. KR-984055 exhibited poor oral bioavailability (7.02 ± 1.58%). The observed oral bioavailabilities of KR-984055 from KR-999001 and KR-999002 were 38.77 ± 2.81% and 39.81 ± 5.25%, respectively. These data were calculated from the levels of free KR-984055 in plasma. Oral KR-999001 and KR-999002 were not recovered from plasma, suggesting that it was readily cleaved to free KR-984055. KR-999001 and KR-999002 appear to be an efficient oral prodrug of KR-984055 that deserved further clinical evaluation in human.

Analyzing the Priority of Leadership Elements for Project Manager of Building Construction Project

“…In order to derive the appropriate leadership elements, we reviewed and organized the leadership elements presented in the precedent literature [19,21,22,23]. Based on reviewing the literature of the leadership, an interview of project managers was carried out, and then the most frequently elements selected were determined as the leadership elements required of project managers, as shown in Figure 4.…”