Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. B, 41-49
Quinolone pharmacokinetics and metabolism H. Lode, G. Hoffken, M. Boeckk, N. Deppermann, K. Bonier and P. Koeppe Medical Department of Klinikum Steglitz, Freie Universit&t Berlin, Hindenburgdamm 30, D-1000 Berlin 45, FRG
Introduction
Many studies have shown that the pharmacokinetics of the quinolone antimicrobials diffeT in many respects from those of most of the other groups of antimicrobial agents. The introduction of fluorine atoms in the C6 position and other varied side chains in positions C, and C, has resulted in increased antibacterial activity and favourable pharmacokinetic properties in the new quinolones with effective serum concentrations, longer elimination half-lives and excellent bioavailability after oral administration. In this overview, the pharmacokinetic properties of new fluorinated quinolones are compared. The results of studies on ofloxacin, ciprofloxacin and fleroxacin conducted in our laboratory (Hoffken et al.t 1985; Borner et al., 1986; Lode et a/., 1987, 1989) have been incorporated into a review of the literature, which also includes available data on enoxacin, norfloxacin and pefloxacin. Since the number offluoroquinolonesis now substantial and continues to grow, a classification system would be useful. One such system (Drusano, 1989) made a classification of these agents by their predominant clearance pathway; other possible systems could depend on different rates of metabolism or on different durations of the elimination half-lives. Methods
There are considerable difficulties in making a comparative analysis of different pharmacokinetic studies, because of differences in methods (e.g. HPLC, bioassays), dosages and modes of administration, non-normalization of body weights, too few volunteers, different compartmental models, etc. However, this overview is mainly based on HPLC measurements and study designs involving oral and parenteral administration in the dosages most widely recommended for each drug. 41 0305-7453/90/26BO41-O9 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
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The pharmacokinetic properties of the new fluoroquinolones are characterized by a high volume of distribution, long biological half-life, low serum protein binding, elimination by renal and extrarenal mechanisms with high total and renal clearances, limited biotransfonnation and moderate to excellent bioavailability after oral administration. However, each quinolone derivative (ciprofloxacin, enoxacin, fleroxacin, norfloxatin, ofloxacdn and pefloxacin) possesses individual pharmacokinetic parameters, which should be considered in the treatment of patients, especially when liver or renal dysfunction exists.
Quinolone
Oral dose (mg)
Ciprofloxacin Enoxacin Fleroxacin Norfloxacin Ofloxacin Pefloxacin
500 400 400 400 400 400
Bioavailability (%) 60-80 80 90-100 35-45 85-95 90-100
c
(ml/1) 1-8-2-8 2-8-3-6 4-4-6-8 1-4-1-8 3-5-5-3 3-8-5-6
(h)
Kd (1)
3-3-5-4 307 175 3-3-5-8 8-9-12-0 no 3-3-5-5 >100 5-0-7-0 90 139 7-5-10-0
; C,,^, maximum plasma concentration; Tl/2, elimination half-life; concentration-time curve.
AUCo-«> (mg/lh) 7-10 16-25 48-78 4-5' 28-35 48-58
•• Clearance Protein iv/oral, 1/h binding total renal (%) 20-40 35 23 14 25 20-30
39-1 21-0 10-1 — 12-8 8-9
21-4 120 6-3 181 10-4 0-42
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Table L Comparison of the pharmacokinetic properties of new quinolones (oral administration)
Route of elimination (% of dose) renal faecal
40-60 65-72 50-65 30-40 70-90 60
15 18 — 28 4 —
volume of distribution; AUC, area under the plasma
Qoloolooe phannacokinetics and metabolism
43
Results
Ofloxacin
Pefloxacin Pefloxacin is a fluoroquinolone that is primarily cleared by the liver. There is only a minor difference from norfloxacin in structure, which alters the half-life and renal handling of pefloxacin, changing it from a compound secreted by the renal tubule to one of which there is net renal tubular reabsorption (Drusano, 1989). Consequently, hepatic extraction and biotransformation dominate the clearance process. Intensive pharmacokinetic studies with pefloxacin were done by Barre, Houin & Tillement (1984), Montay, Gueffon & Roquet (1984) Frydman et al. (1986) and Wise et al. Table II. Phannacokinetics of new quinolones (parenteral administration)
Quinolone Ciprofloxacin Enoxacin Fleroxacin Ofloxacin Pefloxacin
Dose (iv) (mg) 200 200 100 200 200
T
m
(h)
3-5 3-3 8-6 4-3 9-7
AUCo^ amg. h]/l) 5-3 5-4 10-2 14-4 23-4
OAg)
am (ml/min)
(ml/min)
2-8 2-9 1-5 1-2 1-9
652 648 168 234 137
357 347 105 190 20
ci,
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Ofloxacjn is the prototype of a renally cleared fluoroquinolone with low metabolism that is available in both oral and intravenous dosing forms (Wolfson & Hooper, 1985). The most widely recommended dosage for orally administered ofloxacin is 200 mg twice daily. However, for comparative purposes, we determined in our studies the pharmacokinetic parameters for a single 400 mg dose. The maximum serum concentrations after 400 mg orally varied between 3-5 and 5-3 mg/1 (Dagrosa, Verho & Malerczyk, 1984, 1986; Lockley, Wise & Dent, 1984; Verho et al., 1985) after an interval of 11-1-4 h. The elimination half-lives of ofloxacin were calculated to be between 5 and 7 h, and the total area under the plasma concentration-time curve was between 28 and 35 mg/1. h (Table I). Renal clearance after oral administration was between 10-2 and 120 1/h and total clearance after 200 mg intravenously was 12-8 1/h (Table II). Thus, the extrarenal clearance of ofloxacin was below 20% of total clearance. In a comparative study of parenteral and oral administration of single ofloxacin doses of 25, 50, 100 and 200 mg, we found an increase in the AUCs in linear relation to the different dosages over the range examined, paralleling the results in the oral dose ranging trials. Protein binding averaged 25±2-5% with no dependence on the drug concentration noted within the range 057-2-1 mg/1. Ofloxacin is mainly eliminated by the kidneys, and 70-90% of the dose could be recovered in urine within 24-48 h after administration. Faecal elimination accounted for only 4% of the dose. Ofloxacin undergoes less biotransformation than other new fluoroquinolones, with desmethylofloxacin and ofloxacin W-oxide being the two major metabolites formed (Table III). However, ofloxacin is excreted largely unchanged, with metabolites accounting for only about 6% of the total dosage (Borner & Lode, 1986).
44
H. Lode etaL Table III. Metabolites of quinolones
Metabolite Oxo Ar-Formyl W-Sulphonyl N-Oxide JV-Acetyl Acetylamino Desethylenyl Amino JV-Demethyl
Ciprofloxacin Enoxacin Fleroxacin Norfloxacin + (M3) + (M4) + (M2)
+ (M4{2))
+ (M1)
+ (M3) + (M2) + (M5)
Ofloxacin Pefloxacin
Modification from Bergan (1988).
(1986). After oral administration, peak concentrations approximated 1-5 mg/1 for the 200 mg dose, 3-2 mg/1 for the 400 mg dose, 5-5 mg/1 for the 600 mg dose, and slightly less than 7 mg/1 for the 800 mg dose. Peak concentrations increased roughly proportionally with the dose. Absorption was rapid at all doses, with peak concentrations occurring at 1-2 h. The terminal elimination half-life ranged from 10-5±2 h (400 mg dose) to 12-6 ±2-5 h (800 mg dose). Urinary recoveries ranged from 111 ±17% of the administered oral dose. Renal clearances ranged from 12-9 to 21-9 ml/min across doses. Total clearances ranged from 111 to 135 ml/min. Thus, non-renal clearance accounted for the vast majority of total drug clearance (Tables I and II). In the examination of the multiple-dose pharmacokinetics of pefloxacin in 12 normal subjects who received 400 mg of pefloxacin either orally or intravenously, the total serum clearance decreased statistically significantly from 123 ml/min for the first dose to 87 ml/min for the last dose. This was associated with a significant increase in the biological elimination halflife from 12 to 14-8 h. These findings suggested that multiple dosing saturated a nonrenal clearance pathway of pefloxacin (Drusano, 1989). The pharmacokinetics of pefloxacin when given intravenously did not differ from the parameters calculated after oral application. AUCs were the same as those observed in the oral studies, indicating that pefloxacin absorption was complete and uninfluenced by the dose. Montay et al. (1984) examined the profile of metabolites in plasma, urine and bile after the administration of pefloxacin to normal volunteers. The major metabolites in serum were pefloxacin W-oxide and JV-desmethylpefloxacin (norfloxacin). The parent compound, pefloxacin A^-oxide, norfloxacin, oxonorfloxacin, oxopefloxacin, and traces of pefloxacin glucuronide were recovered in urine (Table III). Over 72 h after an 800 mg dose, the total urinary recovery of the parent compound plus metabolites accounted for 58-9 ± 8 1 % of the administered dose. Pefloxacin concentrations in bile were 10-20 mg/1 at 2-12 h after the administration of 800 mg of pefloxacin. Sorgel (1989) found 23-2±6% of the desmethyl metabolite and 20-2±1-0% of the W-oxide metabolite after single dose administration of 800 mg pefloxacin orally. The urinary excretion of norfloxacin after a single dose of 600 mg pefloxacin iv in 12 volunteers was 16-2 ± 1-9% of dose (Zurcher et al., 1989).
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( = norfl) Glucuronide
Qninolone pharmacokinetks and metabolism
45
Norfloxacin
Ciprofloxacin Ciprofloxacin, like norfloxacin, is cleared by balanced renal and nonrcnal mechanisms. This compound is available in both oral and parenteral formulations. The oral dosage most widely recommended for this drug is 500 mg twice daily. After oral administration of ciprofloxacin, 500 mg on an empty stomach, the maximal serum concentration varied between 1-51 and 2-77 mg/1 (Bergan et al., 1986; Borner et al., 1986). The time to peak concentration varied between 71 and 92 min, and the elimination half-lives were calculated to be between 2-51 and 5-42 h. Drusano et al. (1986) reported an elimination half-life of 411 ±0-74 h after an oral dose of 200 mg. Volumes of distribution are usually high and were calculated as 3-5-4-8 I/kg after oral administration and 2-32-2-80 I/kg after intravenous administration. In our studies, renal clearance after oral administration of ciprofloxacin was 18-5 l/h and after intravenous administration (200 mg) values between 21-4 and 16-5 l/h were calculated (HofTken et al., 1985; Drusano et al., 1986). Total body clearance varied between 39-1 and 25-2 l/h, resulting in a very high extrarenal clearance, which accounted for 45-35% of the total clearance. Total AUC varied between 6-78 and 9-81 mg/1. h. Serum protein binding was between 20 and 35%. The bioavailability of ciprofloxacin has been calculated between 52% and 84%, Beermann et al. (1986) reported a value of 71% after administering radiolabelled ciprofloxacin to volunteers. After oral administration, 26-35% of the dosage was eliminated by the kidneys, whereas after parenteral administration, 53-61% of the dose was recovered in urine (Tables I and II). One-third to one-half of the serum clearance of ciprofloxacin is accounted for by nonrenal mechanisms. Four metabolites have been characterized (Drusano, 1989).
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Norfloxacin was the first fluoroquinolone available for clinical use in most countries in Western Europe and the United States; it is available only as an oral formulation. Maximum serum concentrations of norfloxacin after 400 mg orally occurred after l-3±0-4h and varied between 1-4 and 1-8 mg/1. The elimination half-life ranged between 3-3 and 7-3 h (Swanson et al., 1983; Eandi et al., 1983). The area under the plasma concentration time curve between 0 and 12 h could be calculated as 4-6 mg/1 • h, but bioavailability was assumed to vary between 35% and 45% of an oral dose. Renal clearance was calculated as 17-4-181 l/h, and since there is no parenteral form of norfloxacin, no data exist on the total clearance. Renal elimination accounts for 25-30% of the dose, and 28% appears in the faeces (Cofsky, DuBouchet & Landesman, 1984; Wise et al., 1986). Edlund et al. (1987) examined the multiple-dose phannacokinetics of norfloxacin in a study in which 200 mg was administered every 12 h for seven days. At the steady state, maximum concentration and the time to the maximum concentration were similar to those reported from single-drug administration. The half-life was 4-2 ±0-6 h, and the AUC from 0 to 12 h at the steady state was 3-2±0-4mg-h/l. Hepatic biotransformation of norfloxacin occurs to some extent. All six metabolites described have modifications in the piperazin ring. The oxo- and ethylenediamine derivatives are the two main metabolites recovered in urine, although cumulative recoveries in urine are low relative to norfloxacin itself. Serum protein binding of norfloxacin is low, about 14%.
46
RLoderta/.
Each of these compounds has limited microbiological activity, usually 1/4 to 1/2 the activity of the parent drug. Beermann et al. (1986) have quantitated the amounts of metabolites formed after intravenous and oral administration of labelled ciprofloxacin. Less than 20% of the administered dose is recoverable as metabolites, even when urine and stool are assayed. Levels of the M-II metabolite are slightly higher after oral administration than after the intravenous route, indicating that limited first-pass hepatic metabolism of ciprofloxacin occurs. After intravenous dosing, 15% of the parent compound is recovered in the stool, indicating elimination across the intestinal wall.
Enoxacin is the first of the new fluoroquinolones that is a naphthiridine, differing from norfloxacin only by the substitution of a nitrogen fluorocarbon at position 8 of the quinolone ring. This substitution improves significantly the bioavailability of this quinolone. Wise et al. (1984), Wolfe/ al. (1984) and Chang et al. (1988) reported on the pharmacokinetics of intravenous and oral enoxacin in healthy volunteers. Maximum serum concentrations of enoxacin after 400 mg orally varied between 2-8 and 3-6 mg/1; after administration of 600 mg orally, a maximum concentration of 3-7 ±0-5 mg/1 was reported. The time to reach maximum serum concentration was calculated at 1-9 ± 1-0 h. Elimination half-lives ranged between 3-3 and 5-8 h, and the area under the possible concentration-time curve was calculated to be between 16 and 22 mg/1 • h. The bioavailability, in comparison of intravenous with oral administration, was 80%. The calculated volume of distribution was 2-5 I/kg. Total body clearance was 210 1/h, and renal clearance was 12-0 1/h, indicating significant extrarenal elimination mechanisms. Serum protein binding ranged from 35% to 40% (Tables I and II). Approximately 50% of the administered dose was recovered as enoxacin in the urine, with concentrations in urine remaining above the MIC for clinically relevant pathogens for at least 24 h. A substantial amount of the oxometabolite was also recovered in the urine, averaging 16% of the 200 mg dose and 11% of the 800 mg dose. Four additional metabolites are known; these are listed in Table III. Fleroxacin Fleroxacin is a trifluorinated quinolone with balanced renal and non renal clearance. Weidekamm et al. (1987) and also our laboratory (Lode, 1989) examined single-dose and multiple-dose pharmacokinetics of different doses of fleroxacin. The terminal halflife was 8-6±l-3 h (100 mg iv) to ll-8±2-8h (1200 mg orally at steady state). Following administration of 400 mg fleroxacin after an overnight fast, a mean maximum concentration in the serum of 5-2 mg/1 was measured approximately 1-3 h after tablet intake; the AUC amounted to 56-2 mgh/1. Some authors (Muth et al., 1989; Singlas et al., 1989) found higher maximum concentrations after 400 mg: between 6-5 and 6-9 mg/1. In the post-distribution phase, the volume of distribution was large and reached 75 1. The total clearance was 127-2 ml/min, and the corresponding value for renal clearance was 61-6 ml/min. The recovery of the parent compound accounted for 50-70% of the dose, with W-desmethyl and TV-oxide metabolites accounting for another 6-5-11% of the administered dose. Tubular secretion did not influence the renal handling of the drug, because the co-administration of probenecid had no effect on the
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Enoxacin
Qrinolone phannacokinetks and metabolism
47
parameters examined. The AUCs for intravenous and oral doses were similar, indicating virtually complete oral absorption (Tables I and II). Protein binding was 23%. Comparative pharmacokinetics
Comparative metabolism The principal metabolic derivatives of the quinolone molecules are demonstrated in Table III. The main nucleus of fluoroquinolone biotransformation is the piperazin ring. The oxoquinolones represent the major metabolites of ciprofloxacin, enoxacin and norfloxacin, with the N-formyl metabolites being the least frequent (Bergan, 1988). Ofloxacin is more stable than the other compounds with less than 5% biotransformation. Pefloxacin stands out in contrast with only 8-10% appearing in the urine as unchanged drug after oral or intravenous dosage; the major products are A^-oxide and desmethylpefloxacin; the latter is identical to norfloxacin, from which all norfloxacin metabolite products are subsequently formed. Sixty percent of ciprofloxacin is eliminated by the kidneys as active drug and 20% as metabolites, after intravenous administration (Borner & Lode, 1986; Bergan, 1988); 15% of the drug is excreted in faeces (10% ciprofloxacin and 5% metabolites) by transintestinal elimination. The main metabolites of ciprofloxacin in urine are sulphociprofloxacin and the oxo-derivative; in faeces also the M2 derivative (sulphociprofloxacin) is the leading compound. Enoxacin is biotransformed to five different metabolites; a substantial amount of the oxometabolite is recovered in the urine, averaging 16% of the 200 mg dose and 11 % of the 800 mg dose.
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The comparative pharmacokinetic parameters of the six newer quinolones discussed here (ciprofloxacin, enoxacin, fleroxacin, norfloxacin, ofloxacin, pefloxacin) are presented in Table I; each substance has specific pharmacokinetic characteristics. Pefloxacin, ofloxacin and fleroxacin have excellent bioavailability and attain high serum concentrations. The bioavailabilities of ciprofloxacin and enoxacin are moderate, whereas norfloxacin, which is used primarily for the treatment of urinary tract infections shows a low to medium bioavailability after oral administration. Elimination half-lives vary between 3-3 and > 11 h. Pefloxacin and fleroxacin display the longest half-lives of 8-11 h. As a result of their long biological half-lives, all new fluoroquinolones can be given once or twice daily. Volumes of distribution are relatively high and vary between 90 1 for ofloxacin and 307 1 for ciprofloxacin. The routes of elimination are mainly through the kidneys, but there are considerable differences between the various substances. Ofloxacin is mainly eliminated via the kidneys and only to a very low extent in the faeces. Conversely, only 30-40%. of orally administered norfloxacin is eliminated through the kidneys, and nearly 30% appears in the faeces. These different routes of elimination are also represented by the clearance values. The extent of extrarenal clearance is different for the six substances, and since the serum clearance of most of these agents is far above the kidney clearance, tubular secretion is an important mechanism in renal clearance. Serum protein binding is low for all six quinolones, and there are no considerable differences between them. As a result of the differences between bioavailability and elimination half-lives of the individual agents, the areas under the plasma concentration time curves also vary considerably.
48
H.LoteetaL
Fleroxacin produces two main metabolites, the W-desmethyl metabolite and the Af-oxide metabolite, which amount to 6-5% of the dose in urine after iv administration and to a maximum of 11-5% after oral administration of 800 mg. This latter finding indicates a slight first-pass effect after oral application. In conclusion it can be stated that there are specific differences in the pharmacokinetic properties of six new quinolones, and these should be considered in patients with disturbed hepatic and renal function as well as in patients with specifically localized infections. Taking antibacterial activities and specific pharmacokinetic characteristics together, further clinical studies may result in specific indication profiles for the different quinolones.
Barre, M., Houin, G. & Tilkment, J. P. (1984). Dose-dependent pharmacokinetic study of pefioxacin, a new antibacterial agent, in humans Journal of Pharmaceutical Science 73, 1379-82. Beermann, D., Scholl, H., Wingender, W., Forster, D., Beubler, E. et al. (1986). Metabolism of ciprofloxacin in man. In First Ciprofloxacin Workshop, Proceedings, (Neu, H. & Weuter, H., eds), Series 34, pp. 141-6. Excerpta Medica, Current Clinical Practice. Bergan, T., Thorsteinsson, S. D., Holstad, I. M. & Johnsen, S. (1986). Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses. European Journal of Clinical
Microbiology 5, 187-92. Bergan, T. (1989). Pharmacokinetics of fluorinatcd quinolones. In The Quinolones (Andriole, V.D., Ed.), pp. 119-54. Academic Press, London. Bomer, K., Hoflken, G., Lode, H., Koeppe, P., Prinzing, C , Glatzel, P. et al. (1986). Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration. European Journal of Clinical Microbiology 5, 179-86. Borner, K. & Lode, H. (1986). Biotransformation von ausgewahlten Gyrasehemmern. Infection 14, Suppl. 1, 54-9. Chang, T., Black, A., Dunky, A., Wolf, R., Sedman, A., Latts, J. et al. (1988). Pharmacokinetics of intravenous and oral enoxacin in healthy volunteers. Journal of Antimicrobial Chemotherapy 21, Suppl. B, 49-56. Cofsky, R. D., DuBouchet, L. & Landesman, S. M. (1984). Recovery of norfloxacin in feces after administration of a single oral dose to human volunteers. Antimicrobial Agents and Chemotherapy 26, 110-1. Dagrosa, E. E., Verho, M. & Malerczyk, V. (1986). Pharmakokinetik von Ofloxacin. Fortschritte in der Antimikrobiellen und Antineoplastischen Chemotherapie 5-5, 819-28. Drusano, G. L. (1989). Pharmacokinetics of the quinolone antimicrobial agents. In Quinolone Antimicrobial Agents (Wolfson, J. S., Hooper, D. C , Eds), pp. 71-106. American Society of Microbiology, Washington, DC. Drusano, G. L., Standiford, H. C , Plaisance, U. J., Forrest, A., Leslie, J. & Caldwell, J. (1986). Absolute oral bioavailability of ciprofloxacin. Antimicrobial Agents and Chemotherapy 30, 444-6. Eandi, M., Viano, I., Di Nola, F., Leone, L. & Genazzani, E. (1983). Pharmacokinetics of norfloxacin in healthy volunteers and patients with renal and hepatic damage. European Journal of Clinical Microbiology 2, 253-9. Edlund, C , Bergan, T., Josefsson, K., Solberg, R. & Nord, C. E. (1987). Effect of norfloxacin on human oropharyngeal and colonic microflora and multiple-dose pharmacokinetics. Scandinavian Journal of Infectious Disease 19, 113-21. Frydman, A. M., Le Roux, Y., Lefebvre, M. A., Djebbar, F., Fourtillan, J. B. & Gaillot, J. (1986). Pharmacokinetics of pefloxacin after repeated intravenous and oral administration (400 mg bid) in young healthy volunteers. Journal of Antimicrobial Chemotherapy 17, Suppl. B, 65-79. Hoffken, G., Lode, H., Prinzing, C , Borner, U. & Koeppe, P. (1985). Pharmacokinetics of ciprofloxacin after oral and parentcraJ administration. Antimicrobial Agents and Chemotherapy 27, 375-9.
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References
Qninolone pharmacoklnetks and
roetaboUsm
49
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Lockley, M. R., Wise, R. & Dent, J. (1984). The pharmacokinetics and tissue penetration of ofioxacin. Journal of Antimicrobial Chemotherapy 14, 647-52. Lode, H. (1989). Pharmacolrinctics and clinical results of parenteially administered new quinolones in humans. Reviews of Infectious Diseases 11, Suppl. 5, S996-S10O4. Lode, H., Hoflken, G., Olschewski, P., Sievers, B., Kirch, A., Borncr, K. et al. (1987). Pharmacokinetics of ofloxacin after parenteral and oral administration. Antimicrobial Agents and Chemotherapy 31, 1338-42. Montay, G., Goueffon, Y. & Roquet, F. (1984). Absorption, distribution, metabolic fate, and elimination of pefloxacin mesylate in mice, rats, dogs, monkeys, and humans. Antimicrobial Agents and Chemotherapy 25, 463-72. Muth, P., Seelmann, R., Gottschalk, B., Stephan, U. & Sorgel, F. (1989). Multiple-dose pharmacokinetics of fleroxacin in healthy volunteers. Reviews of Infectious Diseases 11, Suppl. 5, S1013. Singlas, E., Leroy, A., Fillastre, J. P., Godin, M. & Moulin, B. (1989). Pharmacokinetics of fleroxacin in healthy volunteers and in uremic patients: evaluation of two assay methods. Reviews of Infectious Diseases 11, Suppl. 5, S1017. Sorgel, F. (1989). Metabolism of gyrase inhibitors. Reviews of Infectious Diseases 11, Suppl. 5, SI 119-29. Swanson, B. N., Boppana, V. K., Vlaysses, P. H., Rotmensch, H. H. & Ferguson, R. K. (1983). Norfloxacin disposition after sequentially increasing oral doses. Antimicrobial Agents and Chemotherapy 23, 284-8. Verho, M., Malerczyk, V., Dagrosa, E. & Korn, A. (1985). Dose linearity and other pharmacokinetics of ofloxacin: a new, broad-spectrum antimicrobial agent. Pharmatherapeutica 4, 376-82. Weidekamm, E., Portmann, R., Suter, K., Partos, C , Dell, D. & Lucker, P. W. (1987). Singleand multiple-dose pharmacokinetics of fleroxacin, a trifluorinated quinolone, in humans. Antimicrobial Agents and Chemotherapy 31, 1909-14. Wise, R., Lockley, R., Dent, J. & Webberley, M. (1984). Pharmacokinetics and tissue penetration of enoxacin. Antimicrobial Agents and Chemotherapy 26, 17-19. Wise, R., Lister, D., McNulty, C. A. M., Griggs, D. & Andrews, J. M. (1986). The comparative pharmacokinetics and tissue penetration of four quinolones including intravenously administered enoxacin. Infection 14, Suppl. 3, S196-S202. Wolf, R., Eberl, R., Dunky, A., Mertz, N., Chang, T., Goulet, J. R. et al. (1984). The clinical pharmacokinetics and tolerance of enoxacin in healthy volunteers. Journal of Antimicrobial Chemotherapy 14, Suppl. C, 63-9. Wolfson, J. S. & Hooper, D. C. (1985). The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. Antimicrobial Agents and Chemotherapy 28, 581-6. Zurcher, J., Jaehde, U., Gottschalk, B., Sorgel, F., Naber, K., Sigl, G. et al. (1989). Effect of dose on bioavailability, pharmacokinetics, and metabolism of pefloxacin following administration of single and multiple doses. Reviews of Infectious Diseases 11, Suppl. 5, S1014-5.
Quinolone pharmacokinetics and metabolism H. Lode, G. Hoffken, M. Boeckk, N. Deppermann, K. Bonier and P. Koeppe Medical Department of Klinikum Steglitz, Freie Universit&t Berlin, Hindenburgdamm 30, D-1000 Berlin 45, FRG
Introduction
Many studies have shown that the pharmacokinetics of the quinolone antimicrobials diffeT in many respects from those of most of the other groups of antimicrobial agents. The introduction of fluorine atoms in the C6 position and other varied side chains in positions C, and C, has resulted in increased antibacterial activity and favourable pharmacokinetic properties in the new quinolones with effective serum concentrations, longer elimination half-lives and excellent bioavailability after oral administration. In this overview, the pharmacokinetic properties of new fluorinated quinolones are compared. The results of studies on ofloxacin, ciprofloxacin and fleroxacin conducted in our laboratory (Hoffken et al.t 1985; Borner et al., 1986; Lode et a/., 1987, 1989) have been incorporated into a review of the literature, which also includes available data on enoxacin, norfloxacin and pefloxacin. Since the number offluoroquinolonesis now substantial and continues to grow, a classification system would be useful. One such system (Drusano, 1989) made a classification of these agents by their predominant clearance pathway; other possible systems could depend on different rates of metabolism or on different durations of the elimination half-lives. Methods
There are considerable difficulties in making a comparative analysis of different pharmacokinetic studies, because of differences in methods (e.g. HPLC, bioassays), dosages and modes of administration, non-normalization of body weights, too few volunteers, different compartmental models, etc. However, this overview is mainly based on HPLC measurements and study designs involving oral and parenteral administration in the dosages most widely recommended for each drug. 41 0305-7453/90/26BO41-O9 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
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The pharmacokinetic properties of the new fluoroquinolones are characterized by a high volume of distribution, long biological half-life, low serum protein binding, elimination by renal and extrarenal mechanisms with high total and renal clearances, limited biotransfonnation and moderate to excellent bioavailability after oral administration. However, each quinolone derivative (ciprofloxacin, enoxacin, fleroxacin, norfloxatin, ofloxacdn and pefloxacin) possesses individual pharmacokinetic parameters, which should be considered in the treatment of patients, especially when liver or renal dysfunction exists.
Quinolone
Oral dose (mg)
Ciprofloxacin Enoxacin Fleroxacin Norfloxacin Ofloxacin Pefloxacin
500 400 400 400 400 400
Bioavailability (%) 60-80 80 90-100 35-45 85-95 90-100
c
(ml/1) 1-8-2-8 2-8-3-6 4-4-6-8 1-4-1-8 3-5-5-3 3-8-5-6
(h)
Kd (1)
3-3-5-4 307 175 3-3-5-8 8-9-12-0 no 3-3-5-5 >100 5-0-7-0 90 139 7-5-10-0
; C,,^, maximum plasma concentration; Tl/2, elimination half-life; concentration-time curve.
AUCo-«> (mg/lh) 7-10 16-25 48-78 4-5' 28-35 48-58
•• Clearance Protein iv/oral, 1/h binding total renal (%) 20-40 35 23 14 25 20-30
39-1 21-0 10-1 — 12-8 8-9
21-4 120 6-3 181 10-4 0-42
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Table L Comparison of the pharmacokinetic properties of new quinolones (oral administration)
Route of elimination (% of dose) renal faecal
40-60 65-72 50-65 30-40 70-90 60
15 18 — 28 4 —
volume of distribution; AUC, area under the plasma
Qoloolooe phannacokinetics and metabolism
43
Results
Ofloxacin
Pefloxacin Pefloxacin is a fluoroquinolone that is primarily cleared by the liver. There is only a minor difference from norfloxacin in structure, which alters the half-life and renal handling of pefloxacin, changing it from a compound secreted by the renal tubule to one of which there is net renal tubular reabsorption (Drusano, 1989). Consequently, hepatic extraction and biotransformation dominate the clearance process. Intensive pharmacokinetic studies with pefloxacin were done by Barre, Houin & Tillement (1984), Montay, Gueffon & Roquet (1984) Frydman et al. (1986) and Wise et al. Table II. Phannacokinetics of new quinolones (parenteral administration)
Quinolone Ciprofloxacin Enoxacin Fleroxacin Ofloxacin Pefloxacin
Dose (iv) (mg) 200 200 100 200 200
T
m
(h)
3-5 3-3 8-6 4-3 9-7
AUCo^ amg. h]/l) 5-3 5-4 10-2 14-4 23-4
OAg)
am (ml/min)
(ml/min)
2-8 2-9 1-5 1-2 1-9
652 648 168 234 137
357 347 105 190 20
ci,
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Ofloxacjn is the prototype of a renally cleared fluoroquinolone with low metabolism that is available in both oral and intravenous dosing forms (Wolfson & Hooper, 1985). The most widely recommended dosage for orally administered ofloxacin is 200 mg twice daily. However, for comparative purposes, we determined in our studies the pharmacokinetic parameters for a single 400 mg dose. The maximum serum concentrations after 400 mg orally varied between 3-5 and 5-3 mg/1 (Dagrosa, Verho & Malerczyk, 1984, 1986; Lockley, Wise & Dent, 1984; Verho et al., 1985) after an interval of 11-1-4 h. The elimination half-lives of ofloxacin were calculated to be between 5 and 7 h, and the total area under the plasma concentration-time curve was between 28 and 35 mg/1. h (Table I). Renal clearance after oral administration was between 10-2 and 120 1/h and total clearance after 200 mg intravenously was 12-8 1/h (Table II). Thus, the extrarenal clearance of ofloxacin was below 20% of total clearance. In a comparative study of parenteral and oral administration of single ofloxacin doses of 25, 50, 100 and 200 mg, we found an increase in the AUCs in linear relation to the different dosages over the range examined, paralleling the results in the oral dose ranging trials. Protein binding averaged 25±2-5% with no dependence on the drug concentration noted within the range 057-2-1 mg/1. Ofloxacin is mainly eliminated by the kidneys, and 70-90% of the dose could be recovered in urine within 24-48 h after administration. Faecal elimination accounted for only 4% of the dose. Ofloxacin undergoes less biotransformation than other new fluoroquinolones, with desmethylofloxacin and ofloxacin W-oxide being the two major metabolites formed (Table III). However, ofloxacin is excreted largely unchanged, with metabolites accounting for only about 6% of the total dosage (Borner & Lode, 1986).
44
H. Lode etaL Table III. Metabolites of quinolones
Metabolite Oxo Ar-Formyl W-Sulphonyl N-Oxide JV-Acetyl Acetylamino Desethylenyl Amino JV-Demethyl
Ciprofloxacin Enoxacin Fleroxacin Norfloxacin + (M3) + (M4) + (M2)
+ (M4{2))
+ (M1)
+ (M3) + (M2) + (M5)
Ofloxacin Pefloxacin
Modification from Bergan (1988).
(1986). After oral administration, peak concentrations approximated 1-5 mg/1 for the 200 mg dose, 3-2 mg/1 for the 400 mg dose, 5-5 mg/1 for the 600 mg dose, and slightly less than 7 mg/1 for the 800 mg dose. Peak concentrations increased roughly proportionally with the dose. Absorption was rapid at all doses, with peak concentrations occurring at 1-2 h. The terminal elimination half-life ranged from 10-5±2 h (400 mg dose) to 12-6 ±2-5 h (800 mg dose). Urinary recoveries ranged from 111 ±17% of the administered oral dose. Renal clearances ranged from 12-9 to 21-9 ml/min across doses. Total clearances ranged from 111 to 135 ml/min. Thus, non-renal clearance accounted for the vast majority of total drug clearance (Tables I and II). In the examination of the multiple-dose pharmacokinetics of pefloxacin in 12 normal subjects who received 400 mg of pefloxacin either orally or intravenously, the total serum clearance decreased statistically significantly from 123 ml/min for the first dose to 87 ml/min for the last dose. This was associated with a significant increase in the biological elimination halflife from 12 to 14-8 h. These findings suggested that multiple dosing saturated a nonrenal clearance pathway of pefloxacin (Drusano, 1989). The pharmacokinetics of pefloxacin when given intravenously did not differ from the parameters calculated after oral application. AUCs were the same as those observed in the oral studies, indicating that pefloxacin absorption was complete and uninfluenced by the dose. Montay et al. (1984) examined the profile of metabolites in plasma, urine and bile after the administration of pefloxacin to normal volunteers. The major metabolites in serum were pefloxacin W-oxide and JV-desmethylpefloxacin (norfloxacin). The parent compound, pefloxacin A^-oxide, norfloxacin, oxonorfloxacin, oxopefloxacin, and traces of pefloxacin glucuronide were recovered in urine (Table III). Over 72 h after an 800 mg dose, the total urinary recovery of the parent compound plus metabolites accounted for 58-9 ± 8 1 % of the administered dose. Pefloxacin concentrations in bile were 10-20 mg/1 at 2-12 h after the administration of 800 mg of pefloxacin. Sorgel (1989) found 23-2±6% of the desmethyl metabolite and 20-2±1-0% of the W-oxide metabolite after single dose administration of 800 mg pefloxacin orally. The urinary excretion of norfloxacin after a single dose of 600 mg pefloxacin iv in 12 volunteers was 16-2 ± 1-9% of dose (Zurcher et al., 1989).
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( = norfl) Glucuronide
Qninolone pharmacokinetks and metabolism
45
Norfloxacin
Ciprofloxacin Ciprofloxacin, like norfloxacin, is cleared by balanced renal and nonrcnal mechanisms. This compound is available in both oral and parenteral formulations. The oral dosage most widely recommended for this drug is 500 mg twice daily. After oral administration of ciprofloxacin, 500 mg on an empty stomach, the maximal serum concentration varied between 1-51 and 2-77 mg/1 (Bergan et al., 1986; Borner et al., 1986). The time to peak concentration varied between 71 and 92 min, and the elimination half-lives were calculated to be between 2-51 and 5-42 h. Drusano et al. (1986) reported an elimination half-life of 411 ±0-74 h after an oral dose of 200 mg. Volumes of distribution are usually high and were calculated as 3-5-4-8 I/kg after oral administration and 2-32-2-80 I/kg after intravenous administration. In our studies, renal clearance after oral administration of ciprofloxacin was 18-5 l/h and after intravenous administration (200 mg) values between 21-4 and 16-5 l/h were calculated (HofTken et al., 1985; Drusano et al., 1986). Total body clearance varied between 39-1 and 25-2 l/h, resulting in a very high extrarenal clearance, which accounted for 45-35% of the total clearance. Total AUC varied between 6-78 and 9-81 mg/1. h. Serum protein binding was between 20 and 35%. The bioavailability of ciprofloxacin has been calculated between 52% and 84%, Beermann et al. (1986) reported a value of 71% after administering radiolabelled ciprofloxacin to volunteers. After oral administration, 26-35% of the dosage was eliminated by the kidneys, whereas after parenteral administration, 53-61% of the dose was recovered in urine (Tables I and II). One-third to one-half of the serum clearance of ciprofloxacin is accounted for by nonrenal mechanisms. Four metabolites have been characterized (Drusano, 1989).
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Norfloxacin was the first fluoroquinolone available for clinical use in most countries in Western Europe and the United States; it is available only as an oral formulation. Maximum serum concentrations of norfloxacin after 400 mg orally occurred after l-3±0-4h and varied between 1-4 and 1-8 mg/1. The elimination half-life ranged between 3-3 and 7-3 h (Swanson et al., 1983; Eandi et al., 1983). The area under the plasma concentration time curve between 0 and 12 h could be calculated as 4-6 mg/1 • h, but bioavailability was assumed to vary between 35% and 45% of an oral dose. Renal clearance was calculated as 17-4-181 l/h, and since there is no parenteral form of norfloxacin, no data exist on the total clearance. Renal elimination accounts for 25-30% of the dose, and 28% appears in the faeces (Cofsky, DuBouchet & Landesman, 1984; Wise et al., 1986). Edlund et al. (1987) examined the multiple-dose phannacokinetics of norfloxacin in a study in which 200 mg was administered every 12 h for seven days. At the steady state, maximum concentration and the time to the maximum concentration were similar to those reported from single-drug administration. The half-life was 4-2 ±0-6 h, and the AUC from 0 to 12 h at the steady state was 3-2±0-4mg-h/l. Hepatic biotransformation of norfloxacin occurs to some extent. All six metabolites described have modifications in the piperazin ring. The oxo- and ethylenediamine derivatives are the two main metabolites recovered in urine, although cumulative recoveries in urine are low relative to norfloxacin itself. Serum protein binding of norfloxacin is low, about 14%.
46
RLoderta/.
Each of these compounds has limited microbiological activity, usually 1/4 to 1/2 the activity of the parent drug. Beermann et al. (1986) have quantitated the amounts of metabolites formed after intravenous and oral administration of labelled ciprofloxacin. Less than 20% of the administered dose is recoverable as metabolites, even when urine and stool are assayed. Levels of the M-II metabolite are slightly higher after oral administration than after the intravenous route, indicating that limited first-pass hepatic metabolism of ciprofloxacin occurs. After intravenous dosing, 15% of the parent compound is recovered in the stool, indicating elimination across the intestinal wall.
Enoxacin is the first of the new fluoroquinolones that is a naphthiridine, differing from norfloxacin only by the substitution of a nitrogen fluorocarbon at position 8 of the quinolone ring. This substitution improves significantly the bioavailability of this quinolone. Wise et al. (1984), Wolfe/ al. (1984) and Chang et al. (1988) reported on the pharmacokinetics of intravenous and oral enoxacin in healthy volunteers. Maximum serum concentrations of enoxacin after 400 mg orally varied between 2-8 and 3-6 mg/1; after administration of 600 mg orally, a maximum concentration of 3-7 ±0-5 mg/1 was reported. The time to reach maximum serum concentration was calculated at 1-9 ± 1-0 h. Elimination half-lives ranged between 3-3 and 5-8 h, and the area under the possible concentration-time curve was calculated to be between 16 and 22 mg/1 • h. The bioavailability, in comparison of intravenous with oral administration, was 80%. The calculated volume of distribution was 2-5 I/kg. Total body clearance was 210 1/h, and renal clearance was 12-0 1/h, indicating significant extrarenal elimination mechanisms. Serum protein binding ranged from 35% to 40% (Tables I and II). Approximately 50% of the administered dose was recovered as enoxacin in the urine, with concentrations in urine remaining above the MIC for clinically relevant pathogens for at least 24 h. A substantial amount of the oxometabolite was also recovered in the urine, averaging 16% of the 200 mg dose and 11% of the 800 mg dose. Four additional metabolites are known; these are listed in Table III. Fleroxacin Fleroxacin is a trifluorinated quinolone with balanced renal and non renal clearance. Weidekamm et al. (1987) and also our laboratory (Lode, 1989) examined single-dose and multiple-dose pharmacokinetics of different doses of fleroxacin. The terminal halflife was 8-6±l-3 h (100 mg iv) to ll-8±2-8h (1200 mg orally at steady state). Following administration of 400 mg fleroxacin after an overnight fast, a mean maximum concentration in the serum of 5-2 mg/1 was measured approximately 1-3 h after tablet intake; the AUC amounted to 56-2 mgh/1. Some authors (Muth et al., 1989; Singlas et al., 1989) found higher maximum concentrations after 400 mg: between 6-5 and 6-9 mg/1. In the post-distribution phase, the volume of distribution was large and reached 75 1. The total clearance was 127-2 ml/min, and the corresponding value for renal clearance was 61-6 ml/min. The recovery of the parent compound accounted for 50-70% of the dose, with W-desmethyl and TV-oxide metabolites accounting for another 6-5-11% of the administered dose. Tubular secretion did not influence the renal handling of the drug, because the co-administration of probenecid had no effect on the
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Enoxacin
Qrinolone phannacokinetks and metabolism
47
parameters examined. The AUCs for intravenous and oral doses were similar, indicating virtually complete oral absorption (Tables I and II). Protein binding was 23%. Comparative pharmacokinetics
Comparative metabolism The principal metabolic derivatives of the quinolone molecules are demonstrated in Table III. The main nucleus of fluoroquinolone biotransformation is the piperazin ring. The oxoquinolones represent the major metabolites of ciprofloxacin, enoxacin and norfloxacin, with the N-formyl metabolites being the least frequent (Bergan, 1988). Ofloxacin is more stable than the other compounds with less than 5% biotransformation. Pefloxacin stands out in contrast with only 8-10% appearing in the urine as unchanged drug after oral or intravenous dosage; the major products are A^-oxide and desmethylpefloxacin; the latter is identical to norfloxacin, from which all norfloxacin metabolite products are subsequently formed. Sixty percent of ciprofloxacin is eliminated by the kidneys as active drug and 20% as metabolites, after intravenous administration (Borner & Lode, 1986; Bergan, 1988); 15% of the drug is excreted in faeces (10% ciprofloxacin and 5% metabolites) by transintestinal elimination. The main metabolites of ciprofloxacin in urine are sulphociprofloxacin and the oxo-derivative; in faeces also the M2 derivative (sulphociprofloxacin) is the leading compound. Enoxacin is biotransformed to five different metabolites; a substantial amount of the oxometabolite is recovered in the urine, averaging 16% of the 200 mg dose and 11 % of the 800 mg dose.
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The comparative pharmacokinetic parameters of the six newer quinolones discussed here (ciprofloxacin, enoxacin, fleroxacin, norfloxacin, ofloxacin, pefloxacin) are presented in Table I; each substance has specific pharmacokinetic characteristics. Pefloxacin, ofloxacin and fleroxacin have excellent bioavailability and attain high serum concentrations. The bioavailabilities of ciprofloxacin and enoxacin are moderate, whereas norfloxacin, which is used primarily for the treatment of urinary tract infections shows a low to medium bioavailability after oral administration. Elimination half-lives vary between 3-3 and > 11 h. Pefloxacin and fleroxacin display the longest half-lives of 8-11 h. As a result of their long biological half-lives, all new fluoroquinolones can be given once or twice daily. Volumes of distribution are relatively high and vary between 90 1 for ofloxacin and 307 1 for ciprofloxacin. The routes of elimination are mainly through the kidneys, but there are considerable differences between the various substances. Ofloxacin is mainly eliminated via the kidneys and only to a very low extent in the faeces. Conversely, only 30-40%. of orally administered norfloxacin is eliminated through the kidneys, and nearly 30% appears in the faeces. These different routes of elimination are also represented by the clearance values. The extent of extrarenal clearance is different for the six substances, and since the serum clearance of most of these agents is far above the kidney clearance, tubular secretion is an important mechanism in renal clearance. Serum protein binding is low for all six quinolones, and there are no considerable differences between them. As a result of the differences between bioavailability and elimination half-lives of the individual agents, the areas under the plasma concentration time curves also vary considerably.
48
H.LoteetaL
Fleroxacin produces two main metabolites, the W-desmethyl metabolite and the Af-oxide metabolite, which amount to 6-5% of the dose in urine after iv administration and to a maximum of 11-5% after oral administration of 800 mg. This latter finding indicates a slight first-pass effect after oral application. In conclusion it can be stated that there are specific differences in the pharmacokinetic properties of six new quinolones, and these should be considered in patients with disturbed hepatic and renal function as well as in patients with specifically localized infections. Taking antibacterial activities and specific pharmacokinetic characteristics together, further clinical studies may result in specific indication profiles for the different quinolones.
Barre, M., Houin, G. & Tilkment, J. P. (1984). Dose-dependent pharmacokinetic study of pefioxacin, a new antibacterial agent, in humans Journal of Pharmaceutical Science 73, 1379-82. Beermann, D., Scholl, H., Wingender, W., Forster, D., Beubler, E. et al. (1986). Metabolism of ciprofloxacin in man. In First Ciprofloxacin Workshop, Proceedings, (Neu, H. & Weuter, H., eds), Series 34, pp. 141-6. Excerpta Medica, Current Clinical Practice. Bergan, T., Thorsteinsson, S. D., Holstad, I. M. & Johnsen, S. (1986). Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses. European Journal of Clinical
Microbiology 5, 187-92. Bergan, T. (1989). Pharmacokinetics of fluorinatcd quinolones. In The Quinolones (Andriole, V.D., Ed.), pp. 119-54. Academic Press, London. Bomer, K., Hoflken, G., Lode, H., Koeppe, P., Prinzing, C , Glatzel, P. et al. (1986). Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration. European Journal of Clinical Microbiology 5, 179-86. Borner, K. & Lode, H. (1986). Biotransformation von ausgewahlten Gyrasehemmern. Infection 14, Suppl. 1, 54-9. Chang, T., Black, A., Dunky, A., Wolf, R., Sedman, A., Latts, J. et al. (1988). Pharmacokinetics of intravenous and oral enoxacin in healthy volunteers. Journal of Antimicrobial Chemotherapy 21, Suppl. B, 49-56. Cofsky, R. D., DuBouchet, L. & Landesman, S. M. (1984). Recovery of norfloxacin in feces after administration of a single oral dose to human volunteers. Antimicrobial Agents and Chemotherapy 26, 110-1. Dagrosa, E. E., Verho, M. & Malerczyk, V. (1986). Pharmakokinetik von Ofloxacin. Fortschritte in der Antimikrobiellen und Antineoplastischen Chemotherapie 5-5, 819-28. Drusano, G. L. (1989). Pharmacokinetics of the quinolone antimicrobial agents. In Quinolone Antimicrobial Agents (Wolfson, J. S., Hooper, D. C , Eds), pp. 71-106. American Society of Microbiology, Washington, DC. Drusano, G. L., Standiford, H. C , Plaisance, U. J., Forrest, A., Leslie, J. & Caldwell, J. (1986). Absolute oral bioavailability of ciprofloxacin. Antimicrobial Agents and Chemotherapy 30, 444-6. Eandi, M., Viano, I., Di Nola, F., Leone, L. & Genazzani, E. (1983). Pharmacokinetics of norfloxacin in healthy volunteers and patients with renal and hepatic damage. European Journal of Clinical Microbiology 2, 253-9. Edlund, C , Bergan, T., Josefsson, K., Solberg, R. & Nord, C. E. (1987). Effect of norfloxacin on human oropharyngeal and colonic microflora and multiple-dose pharmacokinetics. Scandinavian Journal of Infectious Disease 19, 113-21. Frydman, A. M., Le Roux, Y., Lefebvre, M. A., Djebbar, F., Fourtillan, J. B. & Gaillot, J. (1986). Pharmacokinetics of pefloxacin after repeated intravenous and oral administration (400 mg bid) in young healthy volunteers. Journal of Antimicrobial Chemotherapy 17, Suppl. B, 65-79. Hoffken, G., Lode, H., Prinzing, C , Borner, U. & Koeppe, P. (1985). Pharmacokinetics of ciprofloxacin after oral and parentcraJ administration. Antimicrobial Agents and Chemotherapy 27, 375-9.
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References
Qninolone pharmacoklnetks and
roetaboUsm
49
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