Phase I study of multiple-dose cefprozil and comparison with cefaclor

Barbhaiya, Rashmi H.; Shukla, Umesh; Gleason, Carol; Shyu, Wen Chyi; Wilber, Richard B.; Martin, R. Russell; Pittman, Kenneth A.

doi:10.1128/aac.34.6.1198

Antimicrob Agents Chemother

1990

DOI: 10.1128/aac.34.6.1198

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Phase I study of multiple-dose cefprozil and comparison with cefaclor

Rashmi H. Barbhaiya

Umesh Shukla

Carol Gleason

et al.

Abstract: The objectives of this study were to assess the safety and tolerance of cefprozil, to characterize the pharmacokinetics of cefprozil after adiinistration of multiple doses of the drug, and to compare these pharmacokinetic parameters with those obtained with cefaclor. The volunteers received 28 doses of 250, 500, or 1,000 mg of cefprozil or 500 mg of cefaclor every 8 h for 10 days. Serial blood samples and the total volume of urine voided by each individual were collected for pharmacokinetic evaluation on days … Show more

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Cited by 41 publications

(33 citation statements)

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“…Cefprozil appears to have a significantly longer halflife (t4/2) than cefaclor (2,3). As a result, cefprozil is expected to have higher and more sustained concentrations in plasma than cefaclor in the postdistribution phase.…”

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confidence: 99%

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Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration

Barbhaiya

Shukla

Gleason

et al. 1990

Antimicrob Agents Chemother

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The pharmacokinetics and tissue penetration, as judged by skin blister fluid, of cefprozil and cefaclor were examined in 12 healthy male volunteers. Doses of 250 and 500 mg of each drug were given to fasting subjects in a crossover fashion. Serially obtained plasma, skin blister fluid, and urine samples were analyzed for cefprozil or cefaclor by validated high-pressure liquid chromatographic methods. After oral administration of 250 and 500 mg of cefprozil, mean concentrations in plasma rose to peak levels (C..) of 6.1 and 11.2 ,g/ml, respectively, and those of cefaclor were 10.6 and 17.3 ,ug/ml, respectively. The elimination half-life of cefprozil (1.3 h) was significantly longer than that of cefaclor (0.6 h), and as a result, the area under the curve for cefprozil was about two times greater than that for cefaclor. Both cephalosporins were primarily excreted unchanged in urine. The mean skin blister Cm. values were 3.0 and 5.8 ,ug/ml for cefprozil and 3.6 and 6.5 ,ug/ml for cefaclor after the 250-and 500-mg oral doses, respectively. The mean Cm. values in skin blister fluid for both cephalosporins were comparable and were significantly lower than the corresponding Cm.., values in plasma. However, the levels of cefprozil and cefaclor in skin blister fluid declined more slowly than they did in plasma. The skin blister fluid half-life estimates for cefprozil were significantly longer than they were for cefaclor. Parallel to the observation in plasma, the mean skin blister fluid areas under the curve for cefprozil were significantly higher than they were for cefaclor. The plasma and skin blister fluid pharmacokinetic analyses suggest that the exposure of humans to cefprozil is significantly greater than that to cefaclor at the same dose.

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confidence: 99%

“…Pharmacokinetic studies conducted in humans indicate that cefprozil is well absorbed by the gastrointestinal tract (1)(2)(3). Cefprozil appears to have a significantly longer halflife (t4/2) than cefaclor (2,3).…”

mentioning

confidence: 99%

Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration

Barbhaiya

Shukla

Gleason

et al. 1990

Antimicrob Agents Chemother

Self Cite

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“…Our data suggest that the absolute bioavailability of cefprozil in dogs is lower than that reported for other oral cephalosporins in humans. Although urinary recovery of cefprozil following oral administration in humans (60 to 70%) is significantly higher (1)(2)(3) than that observed in dogs (40%), the data from this study raise a need to evaluate the fraction of the orally administered dose absorbed and the absolute bioavailability of this new oral cephalosporin in humans.…”

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confidence: 99%

“…Cefprozil, like other oral cephalosporins, is also well absorbed after oral administration (1-3) in humans. However, urinary recovery accounts for about 60% of the administered dose of cefprozil (1)(2)(3). It appears that cefprozil is incompletely absorbed, is metabolized, and/or is eliminated via biliary excretion in humans.…”

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confidence: 99%

“…A 5.0-ml portion of the urine sample was then transferred to a polypropylene tube containing 5.0 ml of sodium acetate buffer (pH 3.6), mixed, and stored at or below -20°C. Plasma and urine samples were assayed for intact cefprozil by using a validated high-performance liquid chromatographic assay with UV detection (2). The lower limits for quantitation of cefprozil in plasma and urine were 0.5 and 2.0 ,ug/ml, respectively.…”

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Absolute bioavailability of cefprozil after oral administration in beagles

Barbhaiya

Wang

Shyu

et al. 1992

Antimicrob Agents Chemother

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The absolute bioavailability of cefprozil, a new oral cephalosporin, in four beagles was evaluated. In this two-way crossover study, each dog received a 125-mg dose of cefprozil either as an oral aqueous solution or as a 15-min intravenous infusion. A high-performance liquid chromatographic assay with UV detection was employed for the determination of cefprozil concentrations in plasma and urine. Key pharmacokinetic parameters were calculated by noncompartmental methods. Cefprozil was well absorbed after oral administration, and peak concentrations of 17.6 to 26.6 ,ug/ml were attained at 60 min after drug administration. The apparent elimination half-life of cefprozil was about 70 min. The renal clearance was about 60% of total body clearance and is suggestive of significant nonrenal clearance. The absolute bioavailability of cefprozil ranged from 67.1 to 79.1% in the dogs.Cefprozil is a new oral cephalosporin with an antibacterial spectrum that includes important gram-positive and gramnegative organisms (4, 6). It is structurally similar to other cephalosporins in that it has a phenylglycine side chain. Cephalosporins with phenylglycine side chains, such as cephalexin and cefadroxil, are almost completely absorbed and undergo minimal metabolism after oral administration (7, 12). As a result, urinary excretion of these cephalosporins accounts for more than 80% of the administered dose (7, 12). Cefprozil, like other oral cephalosporins, is also well absorbed after oral administration (1-3) in humans. However, urinary recovery accounts for about 60% of the administered dose of cefprozil (1-3). It appears that cefprozil is incompletely absorbed, is metabolized, and/or is eliminated via biliary excretion in humans. The extent of oral absorption of cefprozil in humans is not known at this time. The present two-way crossover study was designed to evaluate absolute bioavailability of orally administered cefprozil in dogs.In a two-way crossover study, four beagles weighing 8 to 12 kg each were administered a 125-mg dose of cefprozil either as an oral aqueous solution or as a 15-min intravenous infusion. There was a 1-week washout period between treatments. The dosing solution was freshly prepared by dissolving 1,000 mg of cefprozil in 200 ml of sterile water. A solution containing 5 mg of cefprozil per ml was filtered through a 0.22-,um-pore-size filter and administered within 2 h of preparation. Food was withheld for about 12 to 14 h prior to dosing and for 4 h after dosing. For intravenous administration of cefprozil, 25 ml of the dosing solution (5 mg/ml) was infused over a 15-min period with a Harvard infusion pump. For oral administration of cefprozil, 25 ml of the dosing solution was administered by gavage through a stomach tube and was followed by 25 ml of tap water to rinse the tube. Blood samples were obtained by saphenous venipuncture just prior to dosing (predose) and at 3, 9, 15 (end of intravenous infusion), 18, 24, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 h after intravenous administration and p...

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An LC‐MS/MS method for simultaneous determination of cefprozil diastereomers in human plasma and its application for the bioequivalence study of two cefprozil tablets in healthy Chinese volunteers

Liu

Zhang

et al. 2015

Biomedical Chromatography

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A rapid and sensitive liquid chromatography-tandem mass spectrometric method was developed for the first time and validated for the determination of cefprozil diastereomers in human plasma. The plasma samples were prepared by protein precipitation using acetonitrile. Detection was performed using an electronic spray ion source in the negative ion mode, operating in the multiple reaction monitoring of the transitions m/z 388.0 to m/z 205.0 for cefprozil diastereomers and m/z 346.1 to m/z 268.1 for cephalexin (the internal standard). The calibration curves of cis-cefprozil and trans-cefprozil were linear in the ranges 0.125-16.0 µg/mL and 0.0403-1.72 µg/mL, respectively. The lower limits of quantification of cis- and trans-cefprozil were 0.125 and 0.0403 µg/mL in human plasma, respectively. The intra- and inter-day precisions of cis- and trans-cefprozil were all <9.7%, and the accuracy ranged from 99.2 to 104.7% and from 100.6 to 102.2%, respectively. The validated method was successfully applied to a bioequivalence study of two cefprozil formulations in 24 healthy Chinese volunteers. The two cefprozil tablets were bioequivalent by measurement of cis-, trans- and total cefprozil. We suggest that the bioequivalence of cefprozil formulations can be evaluated only using cis-cefprozil as the analyte in future studies.

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Phase I study of multiple-dose cefprozil and comparison with cefaclor

Cited by 41 publications

References 16 publications

Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration

Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration

Absolute bioavailability of cefprozil after oral administration in beagles

An LC‐MS/MS method for simultaneous determination of cefprozil diastereomers in human plasma and its application for the bioequivalence study of two cefprozil tablets in healthy Chinese volunteers

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