Pharmacology of Cefuroxime as the 1-acetoxyethyl ester in volunteers

Abstract

Cefuroxime axetil is a new orally absorbed prodrug of the antibiotic cefuroxime. The results of pharmacological studies in 52 healthy volunteers are presented. Intact cefuroxime axetil was not detected in the systemic circulation, indicating that deesterification to yield cefuroxime occurs rapidly after absorption. The bioavailability as measured by urinary recovery of cefuroxime was 40 to 50% if the drug was taken after food and 30% if the drug was taken after overnight fasting. Absorption was similar for three different formulations at 500 mg and independent of dose over the range of 250 mg to 1 g. When the drug was taken after food, serum levels and urinary recoveries were significantly greater for cefuroxime than for ampicillin, but when the drug was taken after fasting the values were similar for the two drugs. The kinetic behavior of cefuroxime axetil and ampicillin was not influenced by repeated dosing at 250 mg. Cefuroxime axetil was well tolerated. Although changes in bowel flora and habit were noted during repeated dosing, these changes were no greater than with ampicillin.Cefuroxime, with its relatively broad antibacterial spectrum and stability to many beta-lactamases, has an established place in antimicrobial therapy (12). However, like many cephalosporins, its application is handicapped by the need for parenteral delivery. Recent work has led to the development of cefuroxime axetil, the 1-acetoxyethyl ester of cefuroxime ( Fig. 1), a derivative which is well absorbed from the gastrointestinal tract and promptly cleaved to cefuroxime thereafter. Preliminary research on cefuroxime axetil indicated that the compound was highly labile in blood and serum, enzymatic deesterification occurring in vitro to produce cefuroxime. To investigate the absorption and pharmacokinetics of cefuroxime axetil, it was necessary to develop an assay method which would extract the drug from blood while simultaneously preventing further enzymatic hydrolysis. The current report summarizes the results of studies designed to determine the concentrations of intact ester in peripheral venous blood, serum levels, and urinary recoveries after single oral doses of 250 mg, 500 mg, and 1 g given to male and female volunteers and the effect offood on absorption. Furthermore, tolerance was assessed during repeated doses of 250 mg given every 6 h in comparison with ampicillin, and the kinetics of cefuroxime and ampicillin were compared at the 250-mg dose level. MATERIALS AND METHODSMetabolism of cefuroxime axetil in vitro. The stability of cefuroxime axetil in blood was determined by adding a known amount of drug to fresh human blood and incubating the mixture for 15 min at 37°C. At 1.5-min intervals during the incubation a sample of blood (0.25 ml) was withdrawn, mixed with acetonitrile (0.5 ml) on a Vortex mixer for 5 s, and then centrifuged at 2,000 rpm for 5 min. The supernatant was assayed for cefuroxime axetil by using high-pressure liquid chromatography (HPLC), and then a sample (0.1 ml) was transferred to another tube, diluted w...

Pharmacokinetics of cefuroxime axetil suspension in infants and children

“…Linear relationships between the dose of cefuroxime axetil and both Cmax and AUC were demonstrated. The enhanced absorption of cefuroxime axetil in the presence of food, as observed by Finn et al (3), is in agreement with the results of other studies (7,10,19). On the basis of these findings, we decided to administer cefuroxime axetil suspension with milk or milk formula in the present study.…”

“…Since cefuroxime sodium is not absorbed orally (4), the 1-acetyloxyethyl ester was substituted for sodium on the cefuroxime molecule to increase its lipid solubility and improve its gastrointestinal absorption. After oral administration, cefuroxime axetil is absorbed and rapidly hydrolyzed by nonspecific esterases in the intestinal mucosa and portal blood (10) to produce concentrations of cefuroxime that exceed the MIC of common respiratory tract pathogens, including 3-lactamasepositive and -negative strains (1,11,12,17).…”

Skin tissue fluid levels of cefotiam in healthy man following oral cefotiam hexetil

“…During absorption, the ester is hydrolysed and the active agent is released [5,8]. In a first clinical study, cefotiam hexeti1300-600 rag/day was effective in 87% patients suffering from bacterial infection of the skin (Kumazawa J, 1987 unpublished data).…”

Pharmacokinetic and Bioequivalence Studies of Oral Cefuroxime Axetil 250 mg Tablets in Healthy Human Subjects

“…After oral administration, cefuroxime axetil is deesterified in the intestinal mucosa and absorbed into the bloodstream as cefuroxime moiety. It has activity against Staphylococcus aureus and other Grampositive cocci, certain members of the family Enterobacteriaceae, and β-lactamase-positive and β-lactamase-negative strains of Haemophilus influenzae [3]. Cefuroxime axetil oral formulations are indicated in the treatment of upper and lower respiratory tract infections, in community acquired pneumonia and in intensive care units [4].…”

“…On oral administration, the bioavailability of the drug is 37% only [3,5], and the absorption of tablet is greater when taken after food i.e. 37% to 52% [6].…”