S184
Pharmacology and Pharmacokinetics of Cefprozil Steven L. Barriere
From the Department of Pharmaceutical Services and Division of Infectious Diseases, Department of Medicine, UCLA Center for Health Sciences, Los Angeles, California
Cefprozil is a new orally administered cephalosporin with in vitro activity similar to those of cefuroxime and cefaclor [1, 2]. In addition, cefprozil displays in vitro activity against penicillin-resistant strains of Streptococcus pneumoniae and activity against certain anaerobes, including Clostridium dif ficile. The chemical structure of cefprozil differs from other orally administered cephalosporins by the presence of a Z propenyl group at position 3 of the molecule (figure 1). Additionally, the presence of a p-hydroxyphenyl group at position 7 confers acid stability to the compound. Cefprozil is administered as a mixture of cis and trans isomers in an approximate ratio of 90:10. Initial Pharmacokinetic Studies
Cefprozil, in single or multiple daily doses ranging from 250 to 1,000 mg, has been studied in healthy volunteers. When Barbhaiya et al. [3] examined the pharmacokinetic disposition of the drug in a dose-escalation fashion, linear pharmacokinetics was exhibited (table 1). Briefly, these investigators showed that maximum plasma concentrations of cefprozil (6.2-17.7 mg/L) were achieved —1 hour after drug • administration. The mean percentage of dose excreted in the urine as unchanged drug ranged from 57% to 70%. In another study [4] by these same investigators, maximum plasma concentrations were achieved 1.5-2 hours after multiple doses were administered. Maximum plasma con-
Reprints or correspondence: Dr. Steven L. Barriere, UCLA Medical Center, 37-121 CHS, Los Angeles, California 90024.
Clinical Infectious Diseases 1992;14(Suppl 2):S184-8 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1406-0041$02.00
centrations associated with the administration of 500-mg and 1,000-mg doses were —9 mg/L and —18 mg/L, respectively. The elimination half-life (q) of cefprozil was —1.25 hours in subjects who had normal renal function. No significant accumulation of the drug was observed when multiple doses were administered every 8 hours [4]. Plasma concentrations >1 mg/L persisted for 6-8 hours after administration of 500-mg and 1,000-mg doses. Cefprozil is excreted primarily by the kidneys as unchanged drug. Since the renal clearance exceeds the glomerular filtration rate, it is likely that active tubular secretion occurs [3, 4]. Concomitant administration with probenecid, as expected, reduces the renal clearance and prolongs the tZ of cefprozil, thus resulting in higher serum concentrations [5]. Shyu et al. [6] also determined the absolute bioavailability of cefprozil by comparing the area under the plasma concentration-vs.-time curve (AUC) and the amount excreted in urine with use of intravenous and oral cefprozil. The AUC and the fraction of the dose excreted in the urine were 33 mg/(L • h) and 35 mg/(L • h) and 71% and 76% for the oral and intravenous doses, respectively. These values indicate an absolute bioavailability of —94% [6]. Barbhaiya and co-workers [7] compared the effect of food on the absorption of cefprozil with that of cefaclor. Both cefprozil and cefaclor were administrated in a single oral dose of 250 mg to healthy subjects under fasting conditions and following a standard breakfast. For cefaclor, both the time to peak plasma concentration as well as the extent of absorption were significantly altered by food, but for the capsule form of cefprozil used in this study, neither was affected [7]. The peak plasma concentration achieved was more markedly reduced for cefaclor (-50%) than for cefprozil (14%). Analysis of the AUC, however, showed a reduction of —12%
Downloaded from http://cid.oxfordjournals.org/ at University of York on July 19, 2015
Cefprozil is a new orally administered cephalosporin with a spectrum of in vitro activity similar to that of cefuroxime. The pharmacokinetics of cefprozil are linear relative to dose size. Gastrointestinal absorption produces maximal plasma concentrations of —10 mg/L 1-2 hours after administration of an oral dose of 500 mg. Approximately 94% of the dose is absorbed, and 60%-70% is excreted in the urine as unchanged drug. The renal clearance exceeds the glomerular filtration rate, thus suggesting active tubular secretion. Administration with food or antacids produces negligible effects on the rate or extent of absorption. Kinetic disposition in the elderly is similar to that in young healthy individuals, but elimination is slightly slower in infants and children. Because renal impairment, but not hepatic dysfunction, significantly reduces the elimination of cefprozil, it is recommended that the dosage be reduced by 50% in patients whose creatinine clearance is
Pharmacology and Pharmacokinetics of Cefprozil Steven L. Barriere
From the Department of Pharmaceutical Services and Division of Infectious Diseases, Department of Medicine, UCLA Center for Health Sciences, Los Angeles, California
Cefprozil is a new orally administered cephalosporin with in vitro activity similar to those of cefuroxime and cefaclor [1, 2]. In addition, cefprozil displays in vitro activity against penicillin-resistant strains of Streptococcus pneumoniae and activity against certain anaerobes, including Clostridium dif ficile. The chemical structure of cefprozil differs from other orally administered cephalosporins by the presence of a Z propenyl group at position 3 of the molecule (figure 1). Additionally, the presence of a p-hydroxyphenyl group at position 7 confers acid stability to the compound. Cefprozil is administered as a mixture of cis and trans isomers in an approximate ratio of 90:10. Initial Pharmacokinetic Studies
Cefprozil, in single or multiple daily doses ranging from 250 to 1,000 mg, has been studied in healthy volunteers. When Barbhaiya et al. [3] examined the pharmacokinetic disposition of the drug in a dose-escalation fashion, linear pharmacokinetics was exhibited (table 1). Briefly, these investigators showed that maximum plasma concentrations of cefprozil (6.2-17.7 mg/L) were achieved —1 hour after drug • administration. The mean percentage of dose excreted in the urine as unchanged drug ranged from 57% to 70%. In another study [4] by these same investigators, maximum plasma concentrations were achieved 1.5-2 hours after multiple doses were administered. Maximum plasma con-
Reprints or correspondence: Dr. Steven L. Barriere, UCLA Medical Center, 37-121 CHS, Los Angeles, California 90024.
Clinical Infectious Diseases 1992;14(Suppl 2):S184-8 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1406-0041$02.00
centrations associated with the administration of 500-mg and 1,000-mg doses were —9 mg/L and —18 mg/L, respectively. The elimination half-life (q) of cefprozil was —1.25 hours in subjects who had normal renal function. No significant accumulation of the drug was observed when multiple doses were administered every 8 hours [4]. Plasma concentrations >1 mg/L persisted for 6-8 hours after administration of 500-mg and 1,000-mg doses. Cefprozil is excreted primarily by the kidneys as unchanged drug. Since the renal clearance exceeds the glomerular filtration rate, it is likely that active tubular secretion occurs [3, 4]. Concomitant administration with probenecid, as expected, reduces the renal clearance and prolongs the tZ of cefprozil, thus resulting in higher serum concentrations [5]. Shyu et al. [6] also determined the absolute bioavailability of cefprozil by comparing the area under the plasma concentration-vs.-time curve (AUC) and the amount excreted in urine with use of intravenous and oral cefprozil. The AUC and the fraction of the dose excreted in the urine were 33 mg/(L • h) and 35 mg/(L • h) and 71% and 76% for the oral and intravenous doses, respectively. These values indicate an absolute bioavailability of —94% [6]. Barbhaiya and co-workers [7] compared the effect of food on the absorption of cefprozil with that of cefaclor. Both cefprozil and cefaclor were administrated in a single oral dose of 250 mg to healthy subjects under fasting conditions and following a standard breakfast. For cefaclor, both the time to peak plasma concentration as well as the extent of absorption were significantly altered by food, but for the capsule form of cefprozil used in this study, neither was affected [7]. The peak plasma concentration achieved was more markedly reduced for cefaclor (-50%) than for cefprozil (14%). Analysis of the AUC, however, showed a reduction of —12%
Downloaded from http://cid.oxfordjournals.org/ at University of York on July 19, 2015
Cefprozil is a new orally administered cephalosporin with a spectrum of in vitro activity similar to that of cefuroxime. The pharmacokinetics of cefprozil are linear relative to dose size. Gastrointestinal absorption produces maximal plasma concentrations of —10 mg/L 1-2 hours after administration of an oral dose of 500 mg. Approximately 94% of the dose is absorbed, and 60%-70% is excreted in the urine as unchanged drug. The renal clearance exceeds the glomerular filtration rate, thus suggesting active tubular secretion. Administration with food or antacids produces negligible effects on the rate or extent of absorption. Kinetic disposition in the elderly is similar to that in young healthy individuals, but elimination is slightly slower in infants and children. Because renal impairment, but not hepatic dysfunction, significantly reduces the elimination of cefprozil, it is recommended that the dosage be reduced by 50% in patients whose creatinine clearance is
