Vol. 34, No. 2
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1990, p. 232-234
0066-4804/90/020232-03$02.00/0 Copyright © 1990, American Society for Microbiology
Pharmacokinetics and Inflammatory Fluid Penetration of Cefpodoxime Proxetil in Volunteers P. O'NEILL, K. NYE, G. DOUCE, J. ANDREWS, AND R. WISE* Department of Medical Microbiology, Dudley Road Hospital, Birmingham B18 7QH, United Kingdom Received 26 June 1989/Accepted 6 November 1989
The pharmacokinetics of cefpodoxime were determined after a single oral dose of 261 mg of cefpodoxime proxetil, equivalent to 200 mg of cefpodoxime, was given to each of six healthy male volunteers. Concentrations in serum, urine, and cantharidin-induced inflammatory fluid were measured by a microbiological assay. The mean peak level in plasma was 2.1 ,ug/ml, attained at a mean time of 2.9 h. The mean half-life of elimination from serum was 2.2 h. The inflammatory exudate was penetrated moderately rapidly, the mean peak level being 1.7 ,ug/ml at 3.5 h. The mean percent penetration of the inflammatory exudate was 103.7. The mean 24-h urine recovery of cefpodoxime was 32.2%. This study suggests that cefpodoxime proxetil taken once or twice daily will be sufficient to treat urinary or systemic infections caused by susceptible pathogens.
Cefpodoximne proxetil (RU 51807; CS 807) [(RS)-1-(isopropyloxycarbonyloxy)ethyl(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-((Z)-methoxyimino)acetamido] -3-methoxymethyl8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate] is a new oral prodrug of a cephalosporin derivative, cefpodoxime (RU 513746). Cefpodoxime proxetil is rapidly and completely hydrolyzed to cefpodoxime during absorption, and no cefpodoxime proxetil is found in serum (B. Lenfant, personal communication). It has been shown to have activity against both gram-negative and gram-positive bacteria (6, 8). Preliminary data suggest that the half-life of cefpodoxime is approximately 2 h and that bioavailability and urinary recovery of the compound are higher after meals (A. Saito, Program Abstr. 27th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 665, 1987). In this study, we investigated the pharmacokinetic properties of cefpodoxime proxetil after a single oral dose and measured its penetration into an inflammatory exudate induced by cantharides plasters (12) in order to ascertain preliminary information about its tissue penetration. The enantiomer and two isomers were not independently studied, since they are bioequivalent (Lenfant, personal communication).
and on the morning of the trial, each subject was given a single 261-mg oral dose of cefpodoxime proxetil (equivalent to 200 mg of cefpodoxime) supplied by Roussel Laboratories, Uxbridge, England (lot no. ET22654/079), in tablet form with 150 ml of water. After 2 h, the subjects had a light breakfast and were allowed to drink freely. Venous blood was sampled via an indwelling intravenous heparin lock catheter at 0, 30, 45, 60, and 90 min and 2, 3, 4, 6, 7, 8, 12, and 26 h postdosing. Inflammatory exudate from the blisters was collected with a micropipette at 30 min and 1, 2, 3, 4, 6, 8, 12, and 26 h. The blisters were resealed by spraying with a fast-drying plastic Nobecutane dressing (Astra Pharmaceuticals Ltd., King's Langley, United Kingdom). Urine was collected from 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24 h postdosing. Antibiotic assays were performed within 1 h of sample collection by a plate diffusion method. The indicator organisms used were Morganella morganii 313 UC3 (Roussel Laboratories) for samples with expected levels of >0.5 ,ug of cefpodoxime per ml and Proteus rettgeri UC 12186 for samples with expected levels of
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1990, p. 232-234
0066-4804/90/020232-03$02.00/0 Copyright © 1990, American Society for Microbiology
Pharmacokinetics and Inflammatory Fluid Penetration of Cefpodoxime Proxetil in Volunteers P. O'NEILL, K. NYE, G. DOUCE, J. ANDREWS, AND R. WISE* Department of Medical Microbiology, Dudley Road Hospital, Birmingham B18 7QH, United Kingdom Received 26 June 1989/Accepted 6 November 1989
The pharmacokinetics of cefpodoxime were determined after a single oral dose of 261 mg of cefpodoxime proxetil, equivalent to 200 mg of cefpodoxime, was given to each of six healthy male volunteers. Concentrations in serum, urine, and cantharidin-induced inflammatory fluid were measured by a microbiological assay. The mean peak level in plasma was 2.1 ,ug/ml, attained at a mean time of 2.9 h. The mean half-life of elimination from serum was 2.2 h. The inflammatory exudate was penetrated moderately rapidly, the mean peak level being 1.7 ,ug/ml at 3.5 h. The mean percent penetration of the inflammatory exudate was 103.7. The mean 24-h urine recovery of cefpodoxime was 32.2%. This study suggests that cefpodoxime proxetil taken once or twice daily will be sufficient to treat urinary or systemic infections caused by susceptible pathogens.
Cefpodoximne proxetil (RU 51807; CS 807) [(RS)-1-(isopropyloxycarbonyloxy)ethyl(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-((Z)-methoxyimino)acetamido] -3-methoxymethyl8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate] is a new oral prodrug of a cephalosporin derivative, cefpodoxime (RU 513746). Cefpodoxime proxetil is rapidly and completely hydrolyzed to cefpodoxime during absorption, and no cefpodoxime proxetil is found in serum (B. Lenfant, personal communication). It has been shown to have activity against both gram-negative and gram-positive bacteria (6, 8). Preliminary data suggest that the half-life of cefpodoxime is approximately 2 h and that bioavailability and urinary recovery of the compound are higher after meals (A. Saito, Program Abstr. 27th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 665, 1987). In this study, we investigated the pharmacokinetic properties of cefpodoxime proxetil after a single oral dose and measured its penetration into an inflammatory exudate induced by cantharides plasters (12) in order to ascertain preliminary information about its tissue penetration. The enantiomer and two isomers were not independently studied, since they are bioequivalent (Lenfant, personal communication).
and on the morning of the trial, each subject was given a single 261-mg oral dose of cefpodoxime proxetil (equivalent to 200 mg of cefpodoxime) supplied by Roussel Laboratories, Uxbridge, England (lot no. ET22654/079), in tablet form with 150 ml of water. After 2 h, the subjects had a light breakfast and were allowed to drink freely. Venous blood was sampled via an indwelling intravenous heparin lock catheter at 0, 30, 45, 60, and 90 min and 2, 3, 4, 6, 7, 8, 12, and 26 h postdosing. Inflammatory exudate from the blisters was collected with a micropipette at 30 min and 1, 2, 3, 4, 6, 8, 12, and 26 h. The blisters were resealed by spraying with a fast-drying plastic Nobecutane dressing (Astra Pharmaceuticals Ltd., King's Langley, United Kingdom). Urine was collected from 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24 h postdosing. Antibiotic assays were performed within 1 h of sample collection by a plate diffusion method. The indicator organisms used were Morganella morganii 313 UC3 (Roussel Laboratories) for samples with expected levels of >0.5 ,ug of cefpodoxime per ml and Proteus rettgeri UC 12186 for samples with expected levels of
