Vol. 36, No. 3
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1992, p. 632-638 0066-4804/92/030632-07$02.00/0 Copyright © 1992, American Society for Microbiology
Fleroxacin Pharmacokinetics in Patients with Liver Cirrhosis ROBERT A. BLOUIN,1* BETTINA A. HAMELIN,' DEBORAH A. SMITH,2 THOMAS S. FOSTER,' WILLIAM J. JOHN,3 AND HORST A. WELKER4 College of Pharnacyl and College of Medicine,3 University of Kentucky, Lexington, Kentucky 40536-0082; SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-09392; and Department of Clinical Research and Pharmaceutical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland4 Received 19 August 1991/Accepted 27 December 1991
In this open-label study, the disposition of fleroxacin in liver disease in 12 healthy male volunteers, 6 male cirrhotics without ascites (group A), and 6 male cirrhotics with ascites (group B) was evaluated. Fleroxacin (400 mg) was administered orally and intravenously to each subject in a random crossover fashion. Fleroxacin was completely absorbed and achieved similar peak concentrations in plasma in all three study groups (P > 0.05). The volume of distribution exceeded 1 liter/kg in healthy controls and was not affected by liver impairment (P > 0.05). Only group B demonstrated differences in the pharmacokinetic parameters evaluated: the systemic and renal clearances of fleroxacin and the renal clearances and clearances of the two major metabolites of fleroxacin formed, N-demethyl fleroxacin and fleroxacin N-oxide, were significantly lower and the half-lives of the parent drug and its metabolites were significantly longer in group B than in healthy controls and group A (P < 0.05). The elimination of the two metabolites appeared to be formation rate limited in all three study groups. It was concluded from this study that a 50% reduction in the fleroxacin maintenance dose in patients with liver disease appears justified only in patients with ascites. However, no change in the fleroxacin loading dose is needed in patients with compromised liver function.
Fleroxacin [6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7(4-methyl-1-piperazinyl)-4-oxo-quinoline-3-carboxylic acid; AM-833; Ro 23-6240] is a new fluoroquinolone derivative. It possesses a broad antibacterial spectrum and potent activity in vitro against gram-positive and gram-negative bacteria (MIC for 90% of isolates, 0.05). cirrholtic group B than in healthy controls (P < 0.01). The CLF )f fleroxacin N-oxide did not correlate well with the antipyrine clearance from the same subjects (r = 0.295; P > 0.05) Fig. 2).
DISCUSSION This study was undertaken to examine the pharmacokinetic c-hanges of fleroxacin, a fluoroquinolone characterized by a Iczng t1,2 and a high bioavailability, in cirrhotic patients with a: nd without ascites. Ass,hown previously (24), the route of administration (i.v. versus oral) did not significantly influence fleroxacin disposition iin any of the three study groups. The pharmacokinetic param eters determined in this study for healthy controls were iin good agreement with previously published data (7, 11,21, 26). The percentage of unchanged fleroxacin excreted in the urine in this study appeared to be consistently lower than t.hat reported by Weidekamm et al. (24, 25). Other investiigators have reported lower or higher values for the perceritage of unchanged fleroxacin excreted (7, 11, 22). The lower urinary recovery of fleroxacin in our investigation is unexp:ilained at this point. However, the CLR determined in this st udy was consistent with previously published results (19). Ove rall, cirrhotics without ascites (cirrhotic group A) had baselixne characteristics and pharmacokinetic parameters similair to those of healthy controls. Group A cirrhotics had only a significantly higher prothrombin time. However, we would expect a reduced production of proteins, including severaLl clotting factors, in liver disease. Cirr hotics with ascites (cirrhotic group B) showed signs of more advanced liver disease with less hepatic reserve, illustr 0.05), implying that N-oxide formation may not be due to P-450 metabolism. When patients with ascites were considered alone in the regression analysis, they showed a better relationship between the antipyrine clearance and the CLF of fleroxacin N-oxide. All patients with ascites had an antipyrine clearance of less than 2 liters/h and were compromised in their ability to form the N-oxide metabolite as well as the N-demethyl metabolite. Therefore, our results propose that the metabolic pathway of the N-oxide metabolite may be affected by severe liver disease. In all three study groups, CLR accounted for approximately 40% and CLF accounted for 7 to 10% of the CLs of fleroxacin, leaving approximately 50% of fleroxacin clearance being unaccounted for. This observation is consistent with those of other studies (7, 22, 24, 26). Since the calculation of CLF is done under the assumption of complete recovery of the metabolite and, in the case of fleroxacin, only 50% of the CLs is accounted for, one should be cautious when interpreting CLF. In summary, fleroxacin was eliminated to a large extent unchanged via renal excretion, and only a negligible amount of parent drug was metabolized by the liver to N-demethyl fleroxacin and fleroxacin N-oxide. No major changes in the
FLEROXACIN PHARMACOKINETICS IN LIVER CIRRHOSIS
VOL. 36, 1992
637
10, 10
A
0 40
1
Immm
8
N dwindrj ftroxmwn
A a
n"
0 ftroxacin 0 N4wns" ftmxadn A Swaxodn N-axide
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i-
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.001
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0
.(
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100
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FIG. 3. Plasma concentration-time profiles of fleroxacin and its two major metabolites for healthy control subjects (A), cirrhotics without ascites (B), and cirrhotics with ascites (C).
pharmacokinetic parameters of fleroxacin occurred in cirrhotics without ascites. The CLs of fleroxacin was significantly lower in cirrhotics with ascites than in healthy controls and cirrhotics without ascites, partly because of significantly lower CLR and CLF in this patient population. Our study results indicate that no dosage changes are necessary in cirrhotics without ascites. In cirrhotics with ascites, the loading dose does not require adjustment; however, a reduced daily maintenance dose, i.e., 200 mg once daily instead of 400 mg once daily, is recommended. ACKNOWLEDGMENTS We acknowledge the invaluable assistance of Peter Heizmann, Jean-Maxime Ducarre, and Ren6e Portmann.
REFERENCES 1. Aoyama, H., M. Inoue, and S. Mitsuhashi. 1988. In-vitro and in-vivo antibacterial activity of fleroxacin, a new fluorinated quinolone. J. Antimicrob. Chemother. 22(Suppl. D):99-114. 2. Bolton, S. 1984. Factorial designs, p. 258-363. In S. Bolton (ed.), Pharmaceutical statistics. Marcel Dekker, Inc., New York.
3. Bremner, D. A., A. S. Dickie, and K. P. Singh. 1988. In-vitro activity of fleroxacin compared with three quinolones. J. Antimicrob. Chemother. 22(Suppl. D):19-23. 4. Chang, S. L., K. Emmick, and P. J. Wedlund. 1986. Characterization of antipyrine autoinduction in the rat utilizing a new microsampling technique for serial blood sample collection. J. Pharm. Sci. 75:456-458. 5. Chin, N.-X., D. C. Brittain, and H. C. Neu. 1986. In vitro activity of Ro 23-6240, a new fluorinated 4-quinoline. Antimicrob. Agents Chemother. 29:675-680. 6. Conn, H. 0. 1981. A peek at the Child-Turcotte classification. Hepatology 1:673-676. 7. De Lepeleire, I., A. Van Elecken, R. Verbesselt, T. B. TjandraMaga, and P. J. De Schepper. 1988. Comparative oral pharmacokinetics of fleroxacin and pefloxacin. J. Antimicrob. Chemother. 22:197-202. 8. Dell, D., C. Partos, and R. Portmann. 1986. The determination of the new trifluorinated quinolone (AM-833, Ro-23-6240), its N-demethyl and N-oxide metabolites in plasma and urine by HPLC with fluorescence detection. Hoffmann-La Roche research report no. B-104'208. Hoffmann-La Roche Inc., Basel, Switzerland. 9. Farrell, G. C., W. G. E. Cooksley, and L. W. Powell. 1979. Drug metabolism in liver disease: activity of hepatic microsomal
638
ANTIMICROB. AGENTS CHEMOTHER.
BLOUIN ET AL.
metabolizing enzymes. Clin. Pharmacol. Ther. 26:483-492. 10. Gibaldi, M., and D. Perrier (ed.). 1982. Pharmacokinetics, p. 45-111. Marcel Dekker, Inc., New York. 11. Griggs, D. J., R. Wise, B. Kirkpatrick, and J. P. Ashby. 1988. The metabolism and pharmacokinetics of fleroxacin in healthy subjects. J. Antimicrob. Chemother. 22(Suppl. D):191-194. 12. Manek, N., J. M. Andrews, and R. Wise. 1986. In vitro activity of Ro 23-6240, a new difluoroquinolone derivative, compared with that of other antimicrobial agents. Antimicrob. Agents Chemother. 30:330-332. 13. McManus, M. E., I. Stupans, W. Burgess, J. A. Koenig, P. de la Hall, and D. J. Birkett. 1987. Flavin-containing monoxygenase activity in human liver microsomes. Drug Metab. Dispos. 15:256-261. 14. Meyer, J., and R. Brandt. 1985. The in vitro protein binding of Ro 23-6240 (AM-833) ih human, dog and rat plasma. Hoffmann-La Roche research report no. B-104'181. Hoffmann-La Roche Inc., Basel, Switzerland. 15. Nakashima, M., M. Kanamaru, T. Uematsu, A. Takiguchi, A. Mizuno, T. Itaya, F. Kawahara, T. Ooie, S. Saito, H. Uchida, and K. Masuzawa. 1988. Clinical pharmacokinetics and tolerance of fleroxacin in healthy male volunteers. J. Antimicrob. Chemother. 22(Suppl. D):133-144. 16. Paganoni, R., C. Herzog, A. Braunsteiner, and P. Hohl. 1988. Fleroxacin: in-vitro activity worldwide against 20,807 clinical isolates and comparison to ciprofloxacin and norfloxacin. J. Antimicrob. Chemother. 22(Suppl. D):3-17. 17. Riggs, D. S., J. A. Guarnieri, and S. Addelman. 1978. Fitting straight lines when both variables are subjects to error. Life Sci. 22:1305-1360. 18. Rowland, M., and T. N. Tozer (ed.). 1989. Clinical pharmacokinetics: concepts and applications, p. 9-48. Lea & Febiger,
21.
22. 23.
24. 25. 26.
27.
28.
Philadelphia. 19. Singlas, E., A. Leroy, E. Sultan, M. Godin, B. Moulin, A. M. Taburet, M. Dhib, and J.-P. Fillastre. 1990. Disposition of fleroxacin, a new trifluoroquinolone, and its metabolites. Pharmacokinetics in renal failure and influence of haemodialysis. Clin. Pharmacokinet. 19:67-79. 20. Sorgel, F., U. Jaehde, K. Naber, and U. Stephan. 1989. Pharma-
29.
30.
cokinetic disposition of quinolones in human body fluids and tissues. Clin. Pharmacokinet. 16:5-24. Sorgel, F., R. Metz, K. Naber, R. Seelmann, and P. Muth. 1988. Pharmacokinetics and body fluid penetration of fleroxacin in healthy volunteers. J. Antimicrob. Chemother. 22(Suppl. D): 155-167. Sorgel, F., R. Seelmann, K. Naber, R. Metz, and P. Muth. 1988. Metabolism of fleroxacin in man. J. Antimicrob. Chemother. 22(Suppl. D):169-178. Teunissen, M. W. E. 1983. Automated HPLC determination of antipyrine and its main metabolites in plasma, saliva and urine, incItding 4,4'-dihydroxyantipyrine. J. Chromatogr. 278:367378. Weidekamm, E., and R. Portmann. 1989. Variation of pharmacokinetic parameters after intravenous and oral administration of fleroxacin. Rev. Infect. Dis. 1l(Suppl. 5):1023. Weidekamm, E., R. Portmann, C. Partos, and D. Dell. 1988. Single and multiple dose pharmacokinetics of fleroxacin. J. Antimicrob. Chemother. 22(Suppl. D):145-154. Weidekamm, E., R. Portmann, K. Suter, C. Partos, D. Dell, and P. W. Lucker. 1987. Single- and multiple-dose pharmacokinetics of fleroxacin, a trifluorinated quinolone, in humans. Antimicrob. Agents Chemother. 31:1909-1914. Welker, H. A., P. Heizmann, R. Portmann, J. M. Ducarre, E. Weidekamm, R. A. Blouin, C. McClain, D. Beattie, J. Farquhar, and R. Kuokko. 1990. Absolute bioavailability and disposition of Ro-23-6240 in healthy subjects and patients with liver cirrhosis. Hoffmann-La Roche research report no. B-155'556. Hoffmann-La Roche Inc., Basel, Switzerland. Wiltshire, H. R., H. Pearson, A. M. Betty, S. R. Harris, C. H. Muirhead, A. G. James, and J. P. Court. 1989. Metabolism of fleroxacin. Rev. Infect. Dis. 11(Suppl. 5):S1130-S1131. Wise, R., B. Kirkpatrick, J. Ashby, and D. J. Griggs. 1987. Pharmacokinetics and tissue penetration of Ro 23-6240, a new trifluoroquinolone. Antimicrob. Agents Chemother. 31:161-163. Wise, R., D. Honeybourne, J. M. Andrews, and J. P. Ashby. 1988. The penetration of fleroxacin into bronchial mucosa. J. Antimicrob. Chemother. 22:203-206.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1992, p. 632-638 0066-4804/92/030632-07$02.00/0 Copyright © 1992, American Society for Microbiology
Fleroxacin Pharmacokinetics in Patients with Liver Cirrhosis ROBERT A. BLOUIN,1* BETTINA A. HAMELIN,' DEBORAH A. SMITH,2 THOMAS S. FOSTER,' WILLIAM J. JOHN,3 AND HORST A. WELKER4 College of Pharnacyl and College of Medicine,3 University of Kentucky, Lexington, Kentucky 40536-0082; SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-09392; and Department of Clinical Research and Pharmaceutical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland4 Received 19 August 1991/Accepted 27 December 1991
In this open-label study, the disposition of fleroxacin in liver disease in 12 healthy male volunteers, 6 male cirrhotics without ascites (group A), and 6 male cirrhotics with ascites (group B) was evaluated. Fleroxacin (400 mg) was administered orally and intravenously to each subject in a random crossover fashion. Fleroxacin was completely absorbed and achieved similar peak concentrations in plasma in all three study groups (P > 0.05). The volume of distribution exceeded 1 liter/kg in healthy controls and was not affected by liver impairment (P > 0.05). Only group B demonstrated differences in the pharmacokinetic parameters evaluated: the systemic and renal clearances of fleroxacin and the renal clearances and clearances of the two major metabolites of fleroxacin formed, N-demethyl fleroxacin and fleroxacin N-oxide, were significantly lower and the half-lives of the parent drug and its metabolites were significantly longer in group B than in healthy controls and group A (P < 0.05). The elimination of the two metabolites appeared to be formation rate limited in all three study groups. It was concluded from this study that a 50% reduction in the fleroxacin maintenance dose in patients with liver disease appears justified only in patients with ascites. However, no change in the fleroxacin loading dose is needed in patients with compromised liver function.
Fleroxacin [6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7(4-methyl-1-piperazinyl)-4-oxo-quinoline-3-carboxylic acid; AM-833; Ro 23-6240] is a new fluoroquinolone derivative. It possesses a broad antibacterial spectrum and potent activity in vitro against gram-positive and gram-negative bacteria (MIC for 90% of isolates, 0.05). cirrholtic group B than in healthy controls (P < 0.01). The CLF )f fleroxacin N-oxide did not correlate well with the antipyrine clearance from the same subjects (r = 0.295; P > 0.05) Fig. 2).
DISCUSSION This study was undertaken to examine the pharmacokinetic c-hanges of fleroxacin, a fluoroquinolone characterized by a Iczng t1,2 and a high bioavailability, in cirrhotic patients with a: nd without ascites. Ass,hown previously (24), the route of administration (i.v. versus oral) did not significantly influence fleroxacin disposition iin any of the three study groups. The pharmacokinetic param eters determined in this study for healthy controls were iin good agreement with previously published data (7, 11,21, 26). The percentage of unchanged fleroxacin excreted in the urine in this study appeared to be consistently lower than t.hat reported by Weidekamm et al. (24, 25). Other investiigators have reported lower or higher values for the perceritage of unchanged fleroxacin excreted (7, 11, 22). The lower urinary recovery of fleroxacin in our investigation is unexp:ilained at this point. However, the CLR determined in this st udy was consistent with previously published results (19). Ove rall, cirrhotics without ascites (cirrhotic group A) had baselixne characteristics and pharmacokinetic parameters similair to those of healthy controls. Group A cirrhotics had only a significantly higher prothrombin time. However, we would expect a reduced production of proteins, including severaLl clotting factors, in liver disease. Cirr hotics with ascites (cirrhotic group B) showed signs of more advanced liver disease with less hepatic reserve, illustr 0.05), implying that N-oxide formation may not be due to P-450 metabolism. When patients with ascites were considered alone in the regression analysis, they showed a better relationship between the antipyrine clearance and the CLF of fleroxacin N-oxide. All patients with ascites had an antipyrine clearance of less than 2 liters/h and were compromised in their ability to form the N-oxide metabolite as well as the N-demethyl metabolite. Therefore, our results propose that the metabolic pathway of the N-oxide metabolite may be affected by severe liver disease. In all three study groups, CLR accounted for approximately 40% and CLF accounted for 7 to 10% of the CLs of fleroxacin, leaving approximately 50% of fleroxacin clearance being unaccounted for. This observation is consistent with those of other studies (7, 22, 24, 26). Since the calculation of CLF is done under the assumption of complete recovery of the metabolite and, in the case of fleroxacin, only 50% of the CLs is accounted for, one should be cautious when interpreting CLF. In summary, fleroxacin was eliminated to a large extent unchanged via renal excretion, and only a negligible amount of parent drug was metabolized by the liver to N-demethyl fleroxacin and fleroxacin N-oxide. No major changes in the
FLEROXACIN PHARMACOKINETICS IN LIVER CIRRHOSIS
VOL. 36, 1992
637
10, 10
A
0 40
1
Immm
8
N dwindrj ftroxmwn
A a
n"
0 ftroxacin 0 N4wns" ftmxadn A Swaxodn N-axide
r. 14.0" 2
i-
.1,
1.1.
8
301°
I .01.
i
a.
.001
20
s0
6o
40
20
100
40 60 TIME (Hours)
TIME (Hours)
10-
I
100
E3 ftroxacin flwoxadn 0 A fbmxacin N-exide
c
I..
s0
o
z
0
.(
a
.1.
a
-0120 20
40
60
80
100
TIME (Hours)
FIG. 3. Plasma concentration-time profiles of fleroxacin and its two major metabolites for healthy control subjects (A), cirrhotics without ascites (B), and cirrhotics with ascites (C).
pharmacokinetic parameters of fleroxacin occurred in cirrhotics without ascites. The CLs of fleroxacin was significantly lower in cirrhotics with ascites than in healthy controls and cirrhotics without ascites, partly because of significantly lower CLR and CLF in this patient population. Our study results indicate that no dosage changes are necessary in cirrhotics without ascites. In cirrhotics with ascites, the loading dose does not require adjustment; however, a reduced daily maintenance dose, i.e., 200 mg once daily instead of 400 mg once daily, is recommended. ACKNOWLEDGMENTS We acknowledge the invaluable assistance of Peter Heizmann, Jean-Maxime Ducarre, and Ren6e Portmann.
REFERENCES 1. Aoyama, H., M. Inoue, and S. Mitsuhashi. 1988. In-vitro and in-vivo antibacterial activity of fleroxacin, a new fluorinated quinolone. J. Antimicrob. Chemother. 22(Suppl. D):99-114. 2. Bolton, S. 1984. Factorial designs, p. 258-363. In S. Bolton (ed.), Pharmaceutical statistics. Marcel Dekker, Inc., New York.
3. Bremner, D. A., A. S. Dickie, and K. P. Singh. 1988. In-vitro activity of fleroxacin compared with three quinolones. J. Antimicrob. Chemother. 22(Suppl. D):19-23. 4. Chang, S. L., K. Emmick, and P. J. Wedlund. 1986. Characterization of antipyrine autoinduction in the rat utilizing a new microsampling technique for serial blood sample collection. J. Pharm. Sci. 75:456-458. 5. Chin, N.-X., D. C. Brittain, and H. C. Neu. 1986. In vitro activity of Ro 23-6240, a new fluorinated 4-quinoline. Antimicrob. Agents Chemother. 29:675-680. 6. Conn, H. 0. 1981. A peek at the Child-Turcotte classification. Hepatology 1:673-676. 7. De Lepeleire, I., A. Van Elecken, R. Verbesselt, T. B. TjandraMaga, and P. J. De Schepper. 1988. Comparative oral pharmacokinetics of fleroxacin and pefloxacin. J. Antimicrob. Chemother. 22:197-202. 8. Dell, D., C. Partos, and R. Portmann. 1986. The determination of the new trifluorinated quinolone (AM-833, Ro-23-6240), its N-demethyl and N-oxide metabolites in plasma and urine by HPLC with fluorescence detection. Hoffmann-La Roche research report no. B-104'208. Hoffmann-La Roche Inc., Basel, Switzerland. 9. Farrell, G. C., W. G. E. Cooksley, and L. W. Powell. 1979. Drug metabolism in liver disease: activity of hepatic microsomal
638
ANTIMICROB. AGENTS CHEMOTHER.
BLOUIN ET AL.
metabolizing enzymes. Clin. Pharmacol. Ther. 26:483-492. 10. Gibaldi, M., and D. Perrier (ed.). 1982. Pharmacokinetics, p. 45-111. Marcel Dekker, Inc., New York. 11. Griggs, D. J., R. Wise, B. Kirkpatrick, and J. P. Ashby. 1988. The metabolism and pharmacokinetics of fleroxacin in healthy subjects. J. Antimicrob. Chemother. 22(Suppl. D):191-194. 12. Manek, N., J. M. Andrews, and R. Wise. 1986. In vitro activity of Ro 23-6240, a new difluoroquinolone derivative, compared with that of other antimicrobial agents. Antimicrob. Agents Chemother. 30:330-332. 13. McManus, M. E., I. Stupans, W. Burgess, J. A. Koenig, P. de la Hall, and D. J. Birkett. 1987. Flavin-containing monoxygenase activity in human liver microsomes. Drug Metab. Dispos. 15:256-261. 14. Meyer, J., and R. Brandt. 1985. The in vitro protein binding of Ro 23-6240 (AM-833) ih human, dog and rat plasma. Hoffmann-La Roche research report no. B-104'181. Hoffmann-La Roche Inc., Basel, Switzerland. 15. Nakashima, M., M. Kanamaru, T. Uematsu, A. Takiguchi, A. Mizuno, T. Itaya, F. Kawahara, T. Ooie, S. Saito, H. Uchida, and K. Masuzawa. 1988. Clinical pharmacokinetics and tolerance of fleroxacin in healthy male volunteers. J. Antimicrob. Chemother. 22(Suppl. D):133-144. 16. Paganoni, R., C. Herzog, A. Braunsteiner, and P. Hohl. 1988. Fleroxacin: in-vitro activity worldwide against 20,807 clinical isolates and comparison to ciprofloxacin and norfloxacin. J. Antimicrob. Chemother. 22(Suppl. D):3-17. 17. Riggs, D. S., J. A. Guarnieri, and S. Addelman. 1978. Fitting straight lines when both variables are subjects to error. Life Sci. 22:1305-1360. 18. Rowland, M., and T. N. Tozer (ed.). 1989. Clinical pharmacokinetics: concepts and applications, p. 9-48. Lea & Febiger,
21.
22. 23.
24. 25. 26.
27.
28.
Philadelphia. 19. Singlas, E., A. Leroy, E. Sultan, M. Godin, B. Moulin, A. M. Taburet, M. Dhib, and J.-P. Fillastre. 1990. Disposition of fleroxacin, a new trifluoroquinolone, and its metabolites. Pharmacokinetics in renal failure and influence of haemodialysis. Clin. Pharmacokinet. 19:67-79. 20. Sorgel, F., U. Jaehde, K. Naber, and U. Stephan. 1989. Pharma-
29.
30.
cokinetic disposition of quinolones in human body fluids and tissues. Clin. Pharmacokinet. 16:5-24. Sorgel, F., R. Metz, K. Naber, R. Seelmann, and P. Muth. 1988. Pharmacokinetics and body fluid penetration of fleroxacin in healthy volunteers. J. Antimicrob. Chemother. 22(Suppl. D): 155-167. Sorgel, F., R. Seelmann, K. Naber, R. Metz, and P. Muth. 1988. Metabolism of fleroxacin in man. J. Antimicrob. Chemother. 22(Suppl. D):169-178. Teunissen, M. W. E. 1983. Automated HPLC determination of antipyrine and its main metabolites in plasma, saliva and urine, incItding 4,4'-dihydroxyantipyrine. J. Chromatogr. 278:367378. Weidekamm, E., and R. Portmann. 1989. Variation of pharmacokinetic parameters after intravenous and oral administration of fleroxacin. Rev. Infect. Dis. 1l(Suppl. 5):1023. Weidekamm, E., R. Portmann, C. Partos, and D. Dell. 1988. Single and multiple dose pharmacokinetics of fleroxacin. J. Antimicrob. Chemother. 22(Suppl. D):145-154. Weidekamm, E., R. Portmann, K. Suter, C. Partos, D. Dell, and P. W. Lucker. 1987. Single- and multiple-dose pharmacokinetics of fleroxacin, a trifluorinated quinolone, in humans. Antimicrob. Agents Chemother. 31:1909-1914. Welker, H. A., P. Heizmann, R. Portmann, J. M. Ducarre, E. Weidekamm, R. A. Blouin, C. McClain, D. Beattie, J. Farquhar, and R. Kuokko. 1990. Absolute bioavailability and disposition of Ro-23-6240 in healthy subjects and patients with liver cirrhosis. Hoffmann-La Roche research report no. B-155'556. Hoffmann-La Roche Inc., Basel, Switzerland. Wiltshire, H. R., H. Pearson, A. M. Betty, S. R. Harris, C. H. Muirhead, A. G. James, and J. P. Court. 1989. Metabolism of fleroxacin. Rev. Infect. Dis. 11(Suppl. 5):S1130-S1131. Wise, R., B. Kirkpatrick, J. Ashby, and D. J. Griggs. 1987. Pharmacokinetics and tissue penetration of Ro 23-6240, a new trifluoroquinolone. Antimicrob. Agents Chemother. 31:161-163. Wise, R., D. Honeybourne, J. M. Andrews, and J. P. Ashby. 1988. The penetration of fleroxacin into bronchial mucosa. J. Antimicrob. Chemother. 22:203-206.
