ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1992, P. 687-689
Vol. 36, No. 3
0066-4804/92/030687-03$02.00/0 Copyright © 1992, American Society for Microbiology
Absolute Bioavailability of Cefprozil after Oral Administration in Beagles RASHMI H. BARBHAIYA,* LOTTE WANG, WEN CHYI SHYU, AND KENNETH A. PITTMAN
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, New York 13221-4755 Received 17 September 1991/Accepted 27 December 1991
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
and 8 h after oral administration. Approximately 5 ml of
spectrum that includes important gram-positive and gramnegative organisms (4, 6). It is structurally similar to other
heparinized blood was obtained at the above-mentioned time points, and the samples were centrifuged, within 30 min of collection, for separation of plasma. The plasma samples
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 predose and 9, 15, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, *
transferred to prelabelled tubes and stored at -20°C. Urine samples were collected via bladder catheters prior to dosing and at intervals of 0 to 4, 4 to 8, and 8 to 24 h after dosing. At the end of the 0- to 4- and 4- to 8-h urine collection intervals, the bladders were flushed with two 10-ml portions of sterile water, and the rinsings were combined with the urine samples for the respective collection interval. The 8- to 24-h urine specimens were collected from the metabolism cage in a container which was then placed over dry ice. The total volume of each urine specimen was measured and recorded. A 5.0-ml portion of the urine sample was then transferred to a polypropylene tube containing 5.0 ml of
were
1000
100 0
z
0
10
0
0)
IL
0.1 0
1
2
3
4
5
6
7
8
9
TIME (HR)
FIG. 1. Mean plasma concentration-versus-time profiles for cefprozil after intravenous (0) and oral (-) administration of a 125-mg dose to beagles.
Corresponding author. 687
688
Route of
administration
Intravenous
Oral
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1. Pharmacokinetics of cefprozil after administration of a single 125-mg dose to beaglesa CLR CLr Vss MRT MAT AUC(a 3) were selected to minimize the mean-square error for the regression. The AUC from time zero to time m, the portion prior to log-linear phase, was calculated by using the linear trapezoidal rule method, and the AUC from time m to the last measurable time point n was calculated by using the log trapezoidal rule method and was extrapolated to infinity. Absolute bioavailability (F) of cefprozil was calculated by using the plasma concentration data as follows: F = (AUCPJAUCj,) x 100, where AUCpO and AUCj, are the AUC O, values after oral and intravenous routes of administration, respectively. The mean concentration-versus-time profiles of cefprozil in plasma after intravenous and oral administration are shown in Fig. 1. Key pharmacokinetic parameters for cefprozil are shown in Table 1. Following oral administration, cefprozil reached a Cmx of 17.6 to 26.6 ,ug/ml within 60 min
F
79.1 78.2 75.4 67.1
CL-r, total
after administration, and measurable concentrations of cefprozil were found at 8 h postdose, which was the time of the last collected sample. The mean absorption time for orally administered cefprozil ranged from 42 to 104 min. Cefprozil levels declined, with an apparent elimination half-life of about 69 to 104 min. The value for the steady-state volume of distribution was about 0.2 liters/kg, indicating that cefprozil was distributed mainly in body water. The renal clearance of cefprozil was approximately 60% of the total body clearance, suggesting that nonrenal clearance plays a significant role in clearing cefprozil from dogs. The majority of cefprozil was excreted in urine during the 0- to 4-h collection period, regardless of the route of administration. Cefprozil was not detectable in the 8- to 24-h urine samples. Overall, 60.9 and 39.5% of the dose was recovered after intravenous and oral administration, respectively. The absolute bioavailability of cefprozil ranged from 67.1 to 79.1% in the four dogs. Oral cephalosporins with a phenylglycine side chain are completely absorbed after oral administration and are excreted primarily in an unchanged form in urine (8-10). The data from the present study with dogs indicate that the absolute bioavailability of cefprozil after oral administration is about 70% and that only 40% of the dose is recovered in urine as intact cefprozil. These data suggest that cefprozil may not be completely absorbed or may be subjected to biliary excretion or presystemic metabolism in dogs. The unabsorbed fraction of an orally administered broad-spectrum antibiotic can disturb the microbial flora of the gastrointestinal tract and can cause gastrointestinal discomfort and diarrhea. Assessment of absolute bioavailability of oral antibiotics is therefore very important. The absolute bioavailability of oral cephalosporins such as cephalexin, cefadroxil, cephradine, and ceftrazine (9, 10) is greater than 90% and suggests complete absorption in humans. 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 (1-3) 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. REFERENCES
1. Barbhaiya, R. H., C. R. Gleason, W. C. Shyu, R. B. Wilber, R. R. Martin, and K. A. Pittman. 1990. Phase I study of single-dose BMY-28100, a new oral cephalosporin. Antimicrob. Agents Chemother. 34:202-205. 2. Barbhaiya, R. H., U. A. Shukla, C. R Gleason, W. C. Shyu, R. B. Wilber, R. R. Martin, and K. A. Pittman. 1990. Phase I
VOL. 36, 1992
3.
4. 5. 6.
7.
study of multiple-dose cefprozil and comparison with cefaclor. Antimicrob. Agents Chemother. 34:1198-1203. Barbhaiya, R. H., U. A. Shukla, C. R. Gleason, W. C. Shyu, R. B. Wilber, and K. A. Pittman. 1990. Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration. Antimicrob. Agents Chemother. 34:1204-1209. Chin, N.-X., and H. C. Neu. 1987. Comparative antibacterial activity of a new oral cephalosporin, BMY-28100. Antimicrob. Agents Chemother. 31:480-483. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed., p. 409-417. Marcel Dekker, Inc., New York. Leitner, F., T. A. Pursiano, R. E. Buck, Y. H. Tsai, D. R. Chisholm, M. Misiek, J. V. Desiderio, and R. E. Kessler. 1987. BMY 28100, a new oral cephalosporin. Antimicrob. Agents Chemother. 31:238-243. Lode, H., R. Stahlmann, and P. Koeppe. 1979. Comparative pharmacokinetics of cephalexin, cefaclor, cefadroxil, and CGP-
NOTES
689
9000. Antimicrob. Agents Chemother. 16:1-6. 8. Nightengale, C. 1980. Pharmacokinetics of the oral cephalosporins. J. Int. Med. Res. 8:(Suppl.):1-8. 9. Nightengale, C. H., D. S. Greene, and R. Quintiliani. 1975. Pharmacokinetics and clinical use of cephalosporin antibiotics. J. Pharm. Sci. 64:1899-1927. 10. Pfeffer, M., R. C. Gaver, and J. Ximenez. 1983. Human intravenous pharmacokinetics and absolute oral bioavailability of cefatrizine. Antimicrob. Agents Chemother. 24:915-920. 11. Reigelman, S., and P. Collier. 1980. The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time. J. Pharmacokinet. Biopharm. 8:509-534. 12. Welling, P. G., S. Dean, A. Selen, M. J. Kendall, and R. Wise. 1979. The pharmacokinetics of the oral cephalosporins cefaclor, cephadine and cephalexin. Int. J. Clin. Pharmacol. Biopharm. 17:397-400.
Vol. 36, No. 3
0066-4804/92/030687-03$02.00/0 Copyright © 1992, American Society for Microbiology
Absolute Bioavailability of Cefprozil after Oral Administration in Beagles RASHMI H. BARBHAIYA,* LOTTE WANG, WEN CHYI SHYU, AND KENNETH A. PITTMAN
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, New York 13221-4755 Received 17 September 1991/Accepted 27 December 1991
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
and 8 h after oral administration. Approximately 5 ml of
spectrum that includes important gram-positive and gramnegative organisms (4, 6). It is structurally similar to other
heparinized blood was obtained at the above-mentioned time points, and the samples were centrifuged, within 30 min of collection, for separation of plasma. The plasma samples
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 predose and 9, 15, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, *
transferred to prelabelled tubes and stored at -20°C. Urine samples were collected via bladder catheters prior to dosing and at intervals of 0 to 4, 4 to 8, and 8 to 24 h after dosing. At the end of the 0- to 4- and 4- to 8-h urine collection intervals, the bladders were flushed with two 10-ml portions of sterile water, and the rinsings were combined with the urine samples for the respective collection interval. The 8- to 24-h urine specimens were collected from the metabolism cage in a container which was then placed over dry ice. The total volume of each urine specimen was measured and recorded. A 5.0-ml portion of the urine sample was then transferred to a polypropylene tube containing 5.0 ml of
were
1000
100 0
z
0
10
0
0)
IL
0.1 0
1
2
3
4
5
6
7
8
9
TIME (HR)
FIG. 1. Mean plasma concentration-versus-time profiles for cefprozil after intravenous (0) and oral (-) administration of a 125-mg dose to beagles.
Corresponding author. 687
688
Route of
administration
Intravenous
Oral
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1. Pharmacokinetics of cefprozil after administration of a single 125-mg dose to beaglesa CLR CLr Vss MRT MAT AUC(a 3) were selected to minimize the mean-square error for the regression. The AUC from time zero to time m, the portion prior to log-linear phase, was calculated by using the linear trapezoidal rule method, and the AUC from time m to the last measurable time point n was calculated by using the log trapezoidal rule method and was extrapolated to infinity. Absolute bioavailability (F) of cefprozil was calculated by using the plasma concentration data as follows: F = (AUCPJAUCj,) x 100, where AUCpO and AUCj, are the AUC O, values after oral and intravenous routes of administration, respectively. The mean concentration-versus-time profiles of cefprozil in plasma after intravenous and oral administration are shown in Fig. 1. Key pharmacokinetic parameters for cefprozil are shown in Table 1. Following oral administration, cefprozil reached a Cmx of 17.6 to 26.6 ,ug/ml within 60 min
F
79.1 78.2 75.4 67.1
CL-r, total
after administration, and measurable concentrations of cefprozil were found at 8 h postdose, which was the time of the last collected sample. The mean absorption time for orally administered cefprozil ranged from 42 to 104 min. Cefprozil levels declined, with an apparent elimination half-life of about 69 to 104 min. The value for the steady-state volume of distribution was about 0.2 liters/kg, indicating that cefprozil was distributed mainly in body water. The renal clearance of cefprozil was approximately 60% of the total body clearance, suggesting that nonrenal clearance plays a significant role in clearing cefprozil from dogs. The majority of cefprozil was excreted in urine during the 0- to 4-h collection period, regardless of the route of administration. Cefprozil was not detectable in the 8- to 24-h urine samples. Overall, 60.9 and 39.5% of the dose was recovered after intravenous and oral administration, respectively. The absolute bioavailability of cefprozil ranged from 67.1 to 79.1% in the four dogs. Oral cephalosporins with a phenylglycine side chain are completely absorbed after oral administration and are excreted primarily in an unchanged form in urine (8-10). The data from the present study with dogs indicate that the absolute bioavailability of cefprozil after oral administration is about 70% and that only 40% of the dose is recovered in urine as intact cefprozil. These data suggest that cefprozil may not be completely absorbed or may be subjected to biliary excretion or presystemic metabolism in dogs. The unabsorbed fraction of an orally administered broad-spectrum antibiotic can disturb the microbial flora of the gastrointestinal tract and can cause gastrointestinal discomfort and diarrhea. Assessment of absolute bioavailability of oral antibiotics is therefore very important. The absolute bioavailability of oral cephalosporins such as cephalexin, cefadroxil, cephradine, and ceftrazine (9, 10) is greater than 90% and suggests complete absorption in humans. 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 (1-3) 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. REFERENCES
1. Barbhaiya, R. H., C. R. Gleason, W. C. Shyu, R. B. Wilber, R. R. Martin, and K. A. Pittman. 1990. Phase I study of single-dose BMY-28100, a new oral cephalosporin. Antimicrob. Agents Chemother. 34:202-205. 2. Barbhaiya, R. H., U. A. Shukla, C. R Gleason, W. C. Shyu, R. B. Wilber, R. R. Martin, and K. A. Pittman. 1990. Phase I
VOL. 36, 1992
3.
4. 5. 6.
7.
study of multiple-dose cefprozil and comparison with cefaclor. Antimicrob. Agents Chemother. 34:1198-1203. Barbhaiya, R. H., U. A. Shukla, C. R. Gleason, W. C. Shyu, R. B. Wilber, and K. A. Pittman. 1990. Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration. Antimicrob. Agents Chemother. 34:1204-1209. Chin, N.-X., and H. C. Neu. 1987. Comparative antibacterial activity of a new oral cephalosporin, BMY-28100. Antimicrob. Agents Chemother. 31:480-483. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed., p. 409-417. Marcel Dekker, Inc., New York. Leitner, F., T. A. Pursiano, R. E. Buck, Y. H. Tsai, D. R. Chisholm, M. Misiek, J. V. Desiderio, and R. E. Kessler. 1987. BMY 28100, a new oral cephalosporin. Antimicrob. Agents Chemother. 31:238-243. Lode, H., R. Stahlmann, and P. Koeppe. 1979. Comparative pharmacokinetics of cephalexin, cefaclor, cefadroxil, and CGP-
NOTES
689
9000. Antimicrob. Agents Chemother. 16:1-6. 8. Nightengale, C. 1980. Pharmacokinetics of the oral cephalosporins. J. Int. Med. Res. 8:(Suppl.):1-8. 9. Nightengale, C. H., D. S. Greene, and R. Quintiliani. 1975. Pharmacokinetics and clinical use of cephalosporin antibiotics. J. Pharm. Sci. 64:1899-1927. 10. Pfeffer, M., R. C. Gaver, and J. Ximenez. 1983. Human intravenous pharmacokinetics and absolute oral bioavailability of cefatrizine. Antimicrob. Agents Chemother. 24:915-920. 11. Reigelman, S., and P. Collier. 1980. The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time. J. Pharmacokinet. Biopharm. 8:509-534. 12. Welling, P. G., S. Dean, A. Selen, M. J. Kendall, and R. Wise. 1979. The pharmacokinetics of the oral cephalosporins cefaclor, cephadine and cephalexin. Int. J. Clin. Pharmacol. Biopharm. 17:397-400.
