Pharmacology Chemotherapy 1991;37:229-238
© 1991S. Karger AG. Basel 0009-3157/91/0374-0229 S 2.75 0
Penetration of Ciprofloxacin and Metabolites into Human Lung, Bronchial and Pleural Tissue after 250 and 500 mg Oral Ciprofloxacin R. Rohwedder\ T. Bergana, E. Carusob, S.B. Thorsteinssonc, H. Della Torred, H. ScholE “ Department of Microbiology, Institute of Pharmacy, University of Oslo, Norway; b Hospital Italiano. Buenos Aires. Argentina; c Department of Medicine, University Hospital, Reykjavik, Iceland; d Hospital Cetrangolo. Vicente Lopez. Argentina; Pharma Research Center, Bayer AG, Wuppertal. FRG
Abstract. Ciprofloxacin (CIP) and metabolite concentrations in lung tissue, parietal pleura and bronchial tissue were assessed in 43 adult patients who underwent lung sur gery. A single oral dose of CIP was given for prophylaxis of bacterial infections. Two to 6 h prior to tissues sampling, 23 patients received 250 mg and 20 subjects 500 mg of the substance. Blood plasma samples were obtained at the same time as the lung tissue sam ples. CIP and its metabolites were assayed chemically by high-pressure liquid chroma tography (HPLC). After 250 mg CIP, the individual lung tissue CIP concentrations dur ing the 2- to 6-hour post-dose period ranged from 0.5 to 4.8 mg/kg. In 20 of the 23 lung samples, the CIP concentrations were above 1 mg/kg. After 500 mg CIP, the correspond ing lung CIP concentrations ranged from 1.6 to 6.0 mg/kg. The CIP lung concentrations were, irrespective of the dose size, between 2 and 7 times higher than the simultaneous blood plasma concentrations. This indicates an excellent penetration of CIP and its me tabolites into lung tissue. Bronchial tissue was obtained in 9 cases. Penetration into bronchial mucosa tissue was good as well, as indicated by tissue/plasma ratio values be tween 1.5 and 4.4. Individual CIP concentrations in the patients given 250 mg CIP, rang ed from 1.0 to 1.6 mg/kg. In the patients who received 500 mg, the range was from 1.7 to 3.4 mg/kg. Tissue/plasma ratio values between 0.8 and 2.1 indicated that penetration to pleural tissues was good as well. Metabolite concentrations in all of the tissues assayed (lung, bronchial mucosa, pleural tissue) were low when compared to the concentrations of CIP. The concentrations in lung, pleural and bronchial tissue will probably permit low doses in the treatment of most respiratory tract infections. The broad spectrum of anti bacterial activity, the good tissue penetration, chemical stability and the good safety rec ord of the substance means that the drug is potentially a useful agent for perioperative antibiotic prophylaxis.
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Key Words. Ciprofloxacin • Metabolites • Oral administration • Lung concentrations • Pleura concentrations • Bronchial concentrations • Pharmacokinetics • Antimicrobials
Rohwcddcr/Bergan/Caruso/Thorsteinsson/Della Torre/Scholl
23«
Introduction
Ciprofloxacin (CIP), a fluorinatcd quinolonc, shows an extremely wide spectrum of activity, which includes gram-negative and gram-positive bacterial species [8, 12, 25, 27]. The substance is chemically very stable over a wide range of pHs and tem peratures as reported by Volkmann and
Table 1. Demographic data of patients given sin gle oral doses of 25« and 500 mg of CIP SD
Range
25« mg (n = 23) Sex (5 females. 18 males) 44.8 Age. years 68.8 Weight, kg Height, cm 168.«
17.3 11.4 7.8
18-72 53-97 155-183
5«« mg (n = 2«) Sex (7 females. 13 males) 44.6 Age, years Weight, kg 69.5 169.6 Height, cm
14.« 16.5 8.«
17-69 44-104 156-184
Characteristics
Mean
Brand [24|, and can be administered both orally and intravenously. These character istics, a good tissue penetration [3, 6, 9, 20, 23] and a good safety record (1, 19] makes the substance well suitable for both pro phylaxis and treatment of infections. CIP reaches tissue concentrations which are several times above the simulta neous blood plasma levels [3, 9, 20, 23], This study aims at comparing concentra tions of CIP and its major metabolites in lung, bronchial and pleural tissues.
Materials and Methods A single oral dose of CIP was given for anti bacterial prophylaxis to patients who underwent lung surgery because of diverse pathology. Twentythree patients received 25« mg and 20 patients 50« mg of CIP, administered between 2 and 6 h before tissue sampling. The personal data of both treatment groups are summarized in table 1. All patients were adults rang ing from 18 to 72 years in the group receiving 25« mg CIP and from 17 to 69 years in the 500 mg group. Lung tissue and blood samples were obtained
Table 2. CIP concentrations in plasma (P). lung tissue (L) and L/P after a single oral dose of CIP Time h
n
Plasma, mg/l
Lung, mg/kg
L/P
mean
SD
mean
SD
Mean
SD
250
2 3 4 5 6
6 3 5 7 2
0.95 0.80 0.75 0.64 0.34
0.48 0.07 0.26 0.18 0.01
2.14 2.15 3.02 1.83 1.29
1.60 0.31 0.59 0.57 0.46
2.54 2.7« 4.45 2.95 3.77
1.71 0.30 1.32 0.67 1.23
500
2 3 4 5 6
4 4 4 4 4
1.64 1.43 1.40 0.79 0.67
0.42 0.44 0.60 0.20 0.22
4.46 5.63 3.88 2.03 2.17
1.25 0.36 0.85 0.15 0.50
2.71 4.35 3.«4 2.75 3.49
0.21 1.35 0.83 0.81 0.94
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Dose mg
Oral Ciprofloxacin in Lung, Bronchial and Pleural Tissue
231
from all 43 patients; parietal pleura was obtained from all who received 250 mg and from 16 patients given 500 mg. Bronchial tissue was obtained in 9 cases of major lung resection mostly due to cancer; in 2 of these cases isolated bronchial mucosa was al so obtained. Blood samples and lung tissues were obtained si multaneously. Plasma and tissue samples were stored at -2 0 °C until they were assayed. An exactly weighed quantity of 200-500 mg tis
sue was added to 5-10 ml of deionized water and was homogenized for 2 min with an Ultra-Turrax (Jahnke and Kunkel). The resulting mixture was freeze-dried and afterwards extracted on a shaker for 2 h with 5 ml of an extraction solution. This solu tion consisted of 12.5 ml of concentrated perchloric acid and 2 g of concentrated phosphoric acid, which were diluted in 500 ml of a solution of acetonitrile and methanol (1:1, v/v). This mixture was brought up to 1.000 ml with distilled water. The supernatant.
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Fig. 1, 2. Concentrations of CIP in plasma and in lung tissue and tissue/plasma ratios after 250 (1) or 500 (2) mg oral CIP.
232_____________________________________ Rohwedder/Bergan/Caruso/Thorsteinsson/Della Torre/Scholl
Dose mg
Time h
n
Plasma, mg/l mean
SD
Pleura, mg/kg
PL/P
mean
SD
Mean
SD
250
2 3 4 5 6
6 3 5 7 2
0.95 0.80 0.75 0.64 0.34
0.48 0.07 0.26 0.18 0.01
6 3 5 7 2
0.65 1.49 0.76 1.01 0.41
0.43 0.75 0.32 0.54 0.09
6 3 5 7 2
0.77 1.81 1.28 1.63 1.21
0.45 0.83 1.07 0.72 0.22
500
2 3 4 5 6
4 4 4 4 4
1.64 1.43 1.40 0.79 0.67
0.42 0.44 0.60 0.20 0.22
4 2 4 3 3
1.33 1.36 2.28 1.74 1.15
0.38 0.37 1.05 1.44 0.80
4 2 4 3 3
0.89 1.09 1.62 1.99 2.15
0.38 0.19 0.20 1.19 1.30
after centrifugation of the homogenate, was filtered through a polytetrafluorethylene membrane filter (pore size 0.45 pm) from Millipore, Bedford, Mass. (USA). Samples were assayed for CIP and metabolites Ml (desethylenyl-ciprofloxacin). M2 (sulfonyl-CIP) and M3 (oxo-CIP) by high-pressure liquid chroma tography (HPLC) using postcolumn dcrivatization [ 21] .
Results
Table 2 and figures 1 and 2 show the mean values and standard deviations (SD) of the CIP concentrations measured in lung tissue and in plasma as well as the lung/plasma concentration ratios (L/P). The individual concentrations in lung tissue, 2-6 h after 250 mg oral CIP ranged from 0.5 to 4.8 mg/kg; in 20 of the 23 lung tissue samples, the concentrations were higher than 1 mg/kg. After 500 mg oral CIP the individual lung tissue CIP concen
trations during the same time period rang ed from 1.6 to 6.0 mg/kg. The CIP concen trations in the lung tissue samples of 40 of the 43 patients, independent of the dosage size, were between 2 and 7 times higher than the simultaneous plasma concentra tions. This indicates an excellent penetra tion of the substance into the lung tissue. After 250 mg CIP, the individual pleu ral tissue CIP concentrations ranged from 0.2 to 2.5 mg/kg during the 2- to 6-hour in terval after the dose (table 3); in 18 of the 23 patients CIP concentrations in pleura were above 0.5 mg/kg. After 500 mg CIP, the range of concentrations in pleural tis sues was from 0.2 to 4.8 mg/kg and was higher than 0.5 mg/kg in 14 of the 16 pa tients. Bronchial CIP concentrations in the pa tients treated with 250 mg CIP ranged from 1.0 to 1.6 mg/kg, and in the patients treated with 500 mg, the range was from 1.7 to 3.4 mg/kg (table 4, fig. 3, 4). As with
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Tabic 3. CIP concentrations in plasma (P), parietal pleura (PL) and L/P after a single oral dose of CIP
233
Oral Ciprofloxacin in Lung, Bronchial and Pleural Tissue
Table 4. CIP concentrations (individual values) in plasma (P). whole bronchial tissue (BW), Bronchial mucosa (BM) and BW/P and BM/P. after a single oral dose of CIP Dose mg
Time h
Patient number
Plasma mg/l
BW mg/kg
BW/P
250
4 5 5 6
37 33 46 42
0.83 0.66 0.87 0.35
1.24 1.09 1.55 0.93
1.49 1.65 1.78 2.66
2 3 4 4 5
18 11 12 14 8
1.18 0.77 1.08 0.96 0.55
2.17 3.40 2.33 2.11 1.73
1.83 4.42 2.16 2.20 3.15
500
BM mg/kg
BM/P
1.82 1.05
2.09 3.00
Table 5. Concentrations (mg/kg) of metabolites (MET) in lung (L) and L/P after a single oral dose of CIP Dose and MET
2h L cone.
250 mg MET 1 MET 2 MET 3
0.013 0.040 0.042
500 mg MET 1 MET 2 MET 3
0.004 0.081 0.100
4h
3h L/P ratio
L cone.
1.624 1.124 1.921
0.016 0.029 0.070
2.125 0.366 0.834
0.042 0.101 0.110
L/P ratio
L cone.
1.861 0.941 0.975
0.037 0.035 0.064
1.885 0.512 0.844
0.030 0.076 0.092
(3)
(6)
L/P ratio
L cone.
3.648 1.236 1.658
0.037 0.030 0.050
2.492 0.596 0.859
0.018 0.035 0.053
L/P ratio
L cone.
3.895 0.818 1.277
0.029 0.026 0.049
1.929 0.560 1.054
0.016 0.024 0.064
(7)
(5)
(4)
(4)
6h
5h
(2) 2.464 0.801 1.056 (4)
(4)
(4)
L/P ratio
1.527 0.342 0.962
the lung tissue, CIP penetrated readily in to bronchial tissue and mucosa. The concentrations of metabolites were extremely low compared to the respective CIP concentrations (tables 5, 6, fig. 5-8).
This conclusion is valid for all the types of tissues and both doses studied. Tissue pen etration of the metabolites 2 and 3 were lower than that of the parent compound and metabolite 1.
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Figures in parentheses show number of samples.
Rohweddcr/Bcrgan/Caruso/Thorstcinsson/Dclla Torrc/Scholl
234
CV¡
201
CL
1. 8 Concentration in mg/l and mg/kg
Q. V H
¡X
Pi
Ql
o «
2S pH Q.
H
i
PAT 37 4 hrs Plasma
Y//A
PAT 46 5 hrs
Bronch. whole
PAT 42 6 hrs
B&Sfl Bronch. mucosa
Concentration in mg/l and mg/kg
□
PAT 33 5 hrs
£öö
b o o r o j * < j > < x o r o i h < 7 >
2 hrs
(111 Metab.
2
3 hrs 4 hrs 5 hrs Hours after dose administration
Metab.1
I
LU 6 hrs
Metab.
B
Fig. 6—8. For legend SCC p. 235.
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3
contribute to enhancing intraphagocytic kill of bacteria [II |. The levels reached af ter the doses studied were several times the MICs of Haemophilus influenzae, pneumococci, Escherichia coli, Klebsiella spp., Enterobacter spp.. Staphylococcus au reus, coagulase-negative staphylococci and enterococci [16, 22, 27]. The good tissue penetration [3, 6, 7, 9, 14, 15, 18, 20, 23] together with the broad spectrum of antibacterial activity [8, 12, 25, 27], chemical stability [24] and the good safety record [1, 19] makes the drug poten tially highly valuable as a primary agent for antibiotic prophylaxis in surgery and for treatment of bronchial and pulmonary infections. Clinical efficacy has been dem onstrated by several well monitored clin ical studies using higher CIP dosage (750 mg, twice daily) [13, 26], medium CIP dosage (500 mg, twice daily) [5, 13. 17], and lower CIP dosage (250 mg twice daily) 12, 4],
4
5
6
7
8
9
Acknowledgement The authors arc grateful to K. Schmidt. R. Mueller and K. Fahsel. Bayer AG. Pharma Forschungsanalytik. for HPLC assay.
10
11
References 12 1 Arcicri. G.; Griffith, E.; Gruenwaldt. G.; Heyd. A.; O'Brien. B.; Becker, N.; August. R.: Cipro floxacin: an update on clinical experience. Am. J. Med. 82: suppl. 4A. pp. 381-386 (1987). 2 Bantz. P.-M.; Grotte. J.: Peters-Haertel. W.: Stahmann, J.: Timm. J.: Kasten. R.; Bruck, H.: Low-dose ciprofloxacin in respiratory tract in fections: a randomized comparison with doxycycline in general practice. Am. J. Med. 82: suppl. 4A. pp. 208-210 (1987). 3 Bergan, T.; Dalhoff, A.; Thorsteinsson. S.B.: in
13
14
15
2.37
Findcy. R. (ed.): Ciprofloxacin. A new 4-quinolone, pp. 23-36 (Sieber & McIntyre. Hong Kong 1985). Brückner. ().; Trautmann. M.: Efficacy and safe ty in the oral treatment of purulent chest disease and pneumonia with cefixime. ofloxacin, and ci profloxacin. J. Chemother. I: suppl. 4. pp. 782783 (1989). Campbell, D.A.: du Bois. R.M.: Clinical efficacy and safety of ciprofloxacin in the treatment of respiratory tract infections. Proc. 1st Int. Cipro floxacin Workshop. Leverkusen 1986. pp. 245247. Caruso, E.; Galimbcrti. R.: Rohwedder, R.: Dif fusion of ciprofloxacin and metabolites into hu man lung tissue after oral and i.v. dosing (Ab stract 223). Int. Congr. for Infect. Dis.. Rio de Janeiro 1988. Caruso, E.: Castro. J.M.; Chamóles. N.; Galimberti. R.: Jorge, L.; Rohwedder. R.: Penetration of ciprofloxacin into human lung tissue after oral and i.v. dosing. J. Chemother. 1: suppl. 4, pp. 549-551 (1989). Chin. N.-X.: Neu. H.C.: Ciprofloxacin, a quinolonc carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 25: 319-326 (1984). Dalhoff. A.: Ciprofloxacin-Konzentrationen in humanen Geweben nach oraler sowie intrave nöser Applikation. Fortschr. Antimikrob. Anti neoplast. Chemother. 6-3: 479-506 (1987). Easmon. C.S.F.; Crane. J.P.: Uptake of ciproflox acin by human neutrophils. J. Antimicrob. Che mother. 16: 67-73 (1985). Easmon. C.S.F.: Crane. J.P.; Blowers. A.: Effect of ciprofloxacin on intracellular organisms: in vi vo and in vitro studies. J. Antimicrob. Chemo ther. !8: suppl. D. pp. 4.3-48 (1987). Fass. R.J.: In vitro activity of ciprofloxacin (Bay o9867). Antimicrob. Agents Chemother. 24: 568574 (1983). Fass. R.J.: Efficacy and safety of oral ciprofloxa cin in the treatment of serious respiratory infec tions. Am. J. Med. 82: suppl. 4A. pp. 202-207 (1987). Honeybourne. D.; Wise, R.; Andrews. J.M.: Ci profloxacin penetration into lungs. Lancet 1040 (1987). Honeybourne. D.; Andrews. J.M.; Ashby. J.P.; Lodwick, R.; Wise R.: Evaluation of the pene-
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Oral Ciprofloxacin in Lung. Bronchial and Pleural Tissue
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17
18
19
20
21
22
Rohwcdder/Bergan/Caruso/Thorstcinsson/Della Torre/Scholl
tration of ciprofloxacin and amoxycillin into the bronchial mucosa. Thorax 43: 715-719 (1988). Hoogkamp-Korstanje. J.A.A.: Comparative in vitro activity of five quinolone derivatives and five other antimicrobial agents used in oral ther apy. Eur. J. Clin. M i c r o b i o l . 333-338 (1984). Hoogkamp-Korstanje, J.A.A.; Klein. S.: Efficacy of ciprofloxacin in ambulant patients with respi ratory tract infections. Proc. 1st Int. Ciprofloxa cin Workshop, Leverkusen 1986. pp. 257-259. Reid. T.M.S.; Gould. I.M.; Goldcr. D.; Lcgge, J.S.; Douglas, J.G.; Friend. J.A.R.; Watt. S.J.: Brief report. Respiratory tract penetration of ci profloxacin. Am. J. Med. 87: suppl. 5A, pp. 6061 (1989). Schacht. P.; Deck. K.; Arcieri, G.; Ryoki, T.: Overview of international clinical studies of ci profloxacin, with special reference to safety. Proc. 1st Int. Ciprofloxacin Workshop, Leverku sen 1986. pp. 435-445. Schlenkhoff. D.; Dalhoff, A.; Knopf. J.; Opfcrkuch. W.: Penetration of ciprofloxacin into hu man lung tissue following intravenous injection. Infection 14: 299-300 (1986). Scholl, H.: Schmidt. K.; Weber, B.: Sensitive and selective determination of picogram amounts of ciprofloxacin and its metabolites in biological samples using high-performance liquid chroma tography and photothermal post-column derivatisation. J. Chromatogr. 416: 321-330 (1987). Shrire, L.; Saunders, J.; Traynor, R.; Koornhof, H.J.: A laboratory assessment of ciprofloxacin and comparable antimicrobial agents. Eur. J. Clin. Microbiol. 3: 328-332 (1984).
23 Unertl, K.; Dicterich, H.J.; Ruckdeschel, G.; Martin. E.; Ehrct, W.; Sundcr-Plassmann, L.: Lung tissue and scrum concentrations of cipro floxacin in patients. 15th Int. Congr. Chemother., Istanbul 1987. 24 Volkmann, D.; Brand, P.: Substance character istics of BAY o9867. Pharma-Report 10608(P) (Bayer AG. Pharma Res. Center, Wuppertal). 25 Wise, R.; Andrews, J.M.; Edwards, L.J.: In vitro activity of Bay o9867, a new quinoline derivative, compared with those of other antimicrobial agents. Antimicrob. Agents Chemother. 23: 559564 (1983). 26 Wollschlager, C.M.; Raoof, S.: Khan, F.A.; Guarncri, J.J.; LaBombardi. V.; Afzal, Q.: Controlled, comparative study of ciprofloxacin versus ampicillin in treatment of bacterial respiratory tract infections. Am. J. Med. 82: suppl. 4A, pp. 164— 168 (1987). 27 Zeiler, H.J.; Grohe, K.: The in vitro and in vivo activity of ciprofloxacin. Eur. J. Clin. Microbiol. 3: 339-343 (1984).
Prof. Dr. Tom Bergan Postbox 1108 Blindem N-0317 Oslo 3 (Norway)
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238
© 1991S. Karger AG. Basel 0009-3157/91/0374-0229 S 2.75 0
Penetration of Ciprofloxacin and Metabolites into Human Lung, Bronchial and Pleural Tissue after 250 and 500 mg Oral Ciprofloxacin R. Rohwedder\ T. Bergana, E. Carusob, S.B. Thorsteinssonc, H. Della Torred, H. ScholE “ Department of Microbiology, Institute of Pharmacy, University of Oslo, Norway; b Hospital Italiano. Buenos Aires. Argentina; c Department of Medicine, University Hospital, Reykjavik, Iceland; d Hospital Cetrangolo. Vicente Lopez. Argentina; Pharma Research Center, Bayer AG, Wuppertal. FRG
Abstract. Ciprofloxacin (CIP) and metabolite concentrations in lung tissue, parietal pleura and bronchial tissue were assessed in 43 adult patients who underwent lung sur gery. A single oral dose of CIP was given for prophylaxis of bacterial infections. Two to 6 h prior to tissues sampling, 23 patients received 250 mg and 20 subjects 500 mg of the substance. Blood plasma samples were obtained at the same time as the lung tissue sam ples. CIP and its metabolites were assayed chemically by high-pressure liquid chroma tography (HPLC). After 250 mg CIP, the individual lung tissue CIP concentrations dur ing the 2- to 6-hour post-dose period ranged from 0.5 to 4.8 mg/kg. In 20 of the 23 lung samples, the CIP concentrations were above 1 mg/kg. After 500 mg CIP, the correspond ing lung CIP concentrations ranged from 1.6 to 6.0 mg/kg. The CIP lung concentrations were, irrespective of the dose size, between 2 and 7 times higher than the simultaneous blood plasma concentrations. This indicates an excellent penetration of CIP and its me tabolites into lung tissue. Bronchial tissue was obtained in 9 cases. Penetration into bronchial mucosa tissue was good as well, as indicated by tissue/plasma ratio values be tween 1.5 and 4.4. Individual CIP concentrations in the patients given 250 mg CIP, rang ed from 1.0 to 1.6 mg/kg. In the patients who received 500 mg, the range was from 1.7 to 3.4 mg/kg. Tissue/plasma ratio values between 0.8 and 2.1 indicated that penetration to pleural tissues was good as well. Metabolite concentrations in all of the tissues assayed (lung, bronchial mucosa, pleural tissue) were low when compared to the concentrations of CIP. The concentrations in lung, pleural and bronchial tissue will probably permit low doses in the treatment of most respiratory tract infections. The broad spectrum of anti bacterial activity, the good tissue penetration, chemical stability and the good safety rec ord of the substance means that the drug is potentially a useful agent for perioperative antibiotic prophylaxis.
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Key Words. Ciprofloxacin • Metabolites • Oral administration • Lung concentrations • Pleura concentrations • Bronchial concentrations • Pharmacokinetics • Antimicrobials
Rohwcddcr/Bergan/Caruso/Thorsteinsson/Della Torre/Scholl
23«
Introduction
Ciprofloxacin (CIP), a fluorinatcd quinolonc, shows an extremely wide spectrum of activity, which includes gram-negative and gram-positive bacterial species [8, 12, 25, 27]. The substance is chemically very stable over a wide range of pHs and tem peratures as reported by Volkmann and
Table 1. Demographic data of patients given sin gle oral doses of 25« and 500 mg of CIP SD
Range
25« mg (n = 23) Sex (5 females. 18 males) 44.8 Age. years 68.8 Weight, kg Height, cm 168.«
17.3 11.4 7.8
18-72 53-97 155-183
5«« mg (n = 2«) Sex (7 females. 13 males) 44.6 Age, years Weight, kg 69.5 169.6 Height, cm
14.« 16.5 8.«
17-69 44-104 156-184
Characteristics
Mean
Brand [24|, and can be administered both orally and intravenously. These character istics, a good tissue penetration [3, 6, 9, 20, 23] and a good safety record (1, 19] makes the substance well suitable for both pro phylaxis and treatment of infections. CIP reaches tissue concentrations which are several times above the simulta neous blood plasma levels [3, 9, 20, 23], This study aims at comparing concentra tions of CIP and its major metabolites in lung, bronchial and pleural tissues.
Materials and Methods A single oral dose of CIP was given for anti bacterial prophylaxis to patients who underwent lung surgery because of diverse pathology. Twentythree patients received 25« mg and 20 patients 50« mg of CIP, administered between 2 and 6 h before tissue sampling. The personal data of both treatment groups are summarized in table 1. All patients were adults rang ing from 18 to 72 years in the group receiving 25« mg CIP and from 17 to 69 years in the 500 mg group. Lung tissue and blood samples were obtained
Table 2. CIP concentrations in plasma (P). lung tissue (L) and L/P after a single oral dose of CIP Time h
n
Plasma, mg/l
Lung, mg/kg
L/P
mean
SD
mean
SD
Mean
SD
250
2 3 4 5 6
6 3 5 7 2
0.95 0.80 0.75 0.64 0.34
0.48 0.07 0.26 0.18 0.01
2.14 2.15 3.02 1.83 1.29
1.60 0.31 0.59 0.57 0.46
2.54 2.7« 4.45 2.95 3.77
1.71 0.30 1.32 0.67 1.23
500
2 3 4 5 6
4 4 4 4 4
1.64 1.43 1.40 0.79 0.67
0.42 0.44 0.60 0.20 0.22
4.46 5.63 3.88 2.03 2.17
1.25 0.36 0.85 0.15 0.50
2.71 4.35 3.«4 2.75 3.49
0.21 1.35 0.83 0.81 0.94
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Dose mg
Oral Ciprofloxacin in Lung, Bronchial and Pleural Tissue
231
from all 43 patients; parietal pleura was obtained from all who received 250 mg and from 16 patients given 500 mg. Bronchial tissue was obtained in 9 cases of major lung resection mostly due to cancer; in 2 of these cases isolated bronchial mucosa was al so obtained. Blood samples and lung tissues were obtained si multaneously. Plasma and tissue samples were stored at -2 0 °C until they were assayed. An exactly weighed quantity of 200-500 mg tis
sue was added to 5-10 ml of deionized water and was homogenized for 2 min with an Ultra-Turrax (Jahnke and Kunkel). The resulting mixture was freeze-dried and afterwards extracted on a shaker for 2 h with 5 ml of an extraction solution. This solu tion consisted of 12.5 ml of concentrated perchloric acid and 2 g of concentrated phosphoric acid, which were diluted in 500 ml of a solution of acetonitrile and methanol (1:1, v/v). This mixture was brought up to 1.000 ml with distilled water. The supernatant.
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Fig. 1, 2. Concentrations of CIP in plasma and in lung tissue and tissue/plasma ratios after 250 (1) or 500 (2) mg oral CIP.
232_____________________________________ Rohwedder/Bergan/Caruso/Thorsteinsson/Della Torre/Scholl
Dose mg
Time h
n
Plasma, mg/l mean
SD
Pleura, mg/kg
PL/P
mean
SD
Mean
SD
250
2 3 4 5 6
6 3 5 7 2
0.95 0.80 0.75 0.64 0.34
0.48 0.07 0.26 0.18 0.01
6 3 5 7 2
0.65 1.49 0.76 1.01 0.41
0.43 0.75 0.32 0.54 0.09
6 3 5 7 2
0.77 1.81 1.28 1.63 1.21
0.45 0.83 1.07 0.72 0.22
500
2 3 4 5 6
4 4 4 4 4
1.64 1.43 1.40 0.79 0.67
0.42 0.44 0.60 0.20 0.22
4 2 4 3 3
1.33 1.36 2.28 1.74 1.15
0.38 0.37 1.05 1.44 0.80
4 2 4 3 3
0.89 1.09 1.62 1.99 2.15
0.38 0.19 0.20 1.19 1.30
after centrifugation of the homogenate, was filtered through a polytetrafluorethylene membrane filter (pore size 0.45 pm) from Millipore, Bedford, Mass. (USA). Samples were assayed for CIP and metabolites Ml (desethylenyl-ciprofloxacin). M2 (sulfonyl-CIP) and M3 (oxo-CIP) by high-pressure liquid chroma tography (HPLC) using postcolumn dcrivatization [ 21] .
Results
Table 2 and figures 1 and 2 show the mean values and standard deviations (SD) of the CIP concentrations measured in lung tissue and in plasma as well as the lung/plasma concentration ratios (L/P). The individual concentrations in lung tissue, 2-6 h after 250 mg oral CIP ranged from 0.5 to 4.8 mg/kg; in 20 of the 23 lung tissue samples, the concentrations were higher than 1 mg/kg. After 500 mg oral CIP the individual lung tissue CIP concen
trations during the same time period rang ed from 1.6 to 6.0 mg/kg. The CIP concen trations in the lung tissue samples of 40 of the 43 patients, independent of the dosage size, were between 2 and 7 times higher than the simultaneous plasma concentra tions. This indicates an excellent penetra tion of the substance into the lung tissue. After 250 mg CIP, the individual pleu ral tissue CIP concentrations ranged from 0.2 to 2.5 mg/kg during the 2- to 6-hour in terval after the dose (table 3); in 18 of the 23 patients CIP concentrations in pleura were above 0.5 mg/kg. After 500 mg CIP, the range of concentrations in pleural tis sues was from 0.2 to 4.8 mg/kg and was higher than 0.5 mg/kg in 14 of the 16 pa tients. Bronchial CIP concentrations in the pa tients treated with 250 mg CIP ranged from 1.0 to 1.6 mg/kg, and in the patients treated with 500 mg, the range was from 1.7 to 3.4 mg/kg (table 4, fig. 3, 4). As with
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Tabic 3. CIP concentrations in plasma (P), parietal pleura (PL) and L/P after a single oral dose of CIP
233
Oral Ciprofloxacin in Lung, Bronchial and Pleural Tissue
Table 4. CIP concentrations (individual values) in plasma (P). whole bronchial tissue (BW), Bronchial mucosa (BM) and BW/P and BM/P. after a single oral dose of CIP Dose mg
Time h
Patient number
Plasma mg/l
BW mg/kg
BW/P
250
4 5 5 6
37 33 46 42
0.83 0.66 0.87 0.35
1.24 1.09 1.55 0.93
1.49 1.65 1.78 2.66
2 3 4 4 5
18 11 12 14 8
1.18 0.77 1.08 0.96 0.55
2.17 3.40 2.33 2.11 1.73
1.83 4.42 2.16 2.20 3.15
500
BM mg/kg
BM/P
1.82 1.05
2.09 3.00
Table 5. Concentrations (mg/kg) of metabolites (MET) in lung (L) and L/P after a single oral dose of CIP Dose and MET
2h L cone.
250 mg MET 1 MET 2 MET 3
0.013 0.040 0.042
500 mg MET 1 MET 2 MET 3
0.004 0.081 0.100
4h
3h L/P ratio
L cone.
1.624 1.124 1.921
0.016 0.029 0.070
2.125 0.366 0.834
0.042 0.101 0.110
L/P ratio
L cone.
1.861 0.941 0.975
0.037 0.035 0.064
1.885 0.512 0.844
0.030 0.076 0.092
(3)
(6)
L/P ratio
L cone.
3.648 1.236 1.658
0.037 0.030 0.050
2.492 0.596 0.859
0.018 0.035 0.053
L/P ratio
L cone.
3.895 0.818 1.277
0.029 0.026 0.049
1.929 0.560 1.054
0.016 0.024 0.064
(7)
(5)
(4)
(4)
6h
5h
(2) 2.464 0.801 1.056 (4)
(4)
(4)
L/P ratio
1.527 0.342 0.962
the lung tissue, CIP penetrated readily in to bronchial tissue and mucosa. The concentrations of metabolites were extremely low compared to the respective CIP concentrations (tables 5, 6, fig. 5-8).
This conclusion is valid for all the types of tissues and both doses studied. Tissue pen etration of the metabolites 2 and 3 were lower than that of the parent compound and metabolite 1.
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Figures in parentheses show number of samples.
Rohweddcr/Bcrgan/Caruso/Thorstcinsson/Dclla Torrc/Scholl
234
CV¡
201
CL
1. 8 Concentration in mg/l and mg/kg
Q. V H
¡X
Pi
Ql
o «
2S pH Q.
H
i
PAT 37 4 hrs Plasma
Y//A
PAT 46 5 hrs
Bronch. whole
PAT 42 6 hrs
B&Sfl Bronch. mucosa
Concentration in mg/l and mg/kg
□
PAT 33 5 hrs
£öö
b o o r o j * < j > < x o r o i h < 7 >
2 hrs
(111 Metab.
2
3 hrs 4 hrs 5 hrs Hours after dose administration
Metab.1
I
LU 6 hrs
Metab.
B
Fig. 6—8. For legend SCC p. 235.
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3
contribute to enhancing intraphagocytic kill of bacteria [II |. The levels reached af ter the doses studied were several times the MICs of Haemophilus influenzae, pneumococci, Escherichia coli, Klebsiella spp., Enterobacter spp.. Staphylococcus au reus, coagulase-negative staphylococci and enterococci [16, 22, 27]. The good tissue penetration [3, 6, 7, 9, 14, 15, 18, 20, 23] together with the broad spectrum of antibacterial activity [8, 12, 25, 27], chemical stability [24] and the good safety record [1, 19] makes the drug poten tially highly valuable as a primary agent for antibiotic prophylaxis in surgery and for treatment of bronchial and pulmonary infections. Clinical efficacy has been dem onstrated by several well monitored clin ical studies using higher CIP dosage (750 mg, twice daily) [13, 26], medium CIP dosage (500 mg, twice daily) [5, 13. 17], and lower CIP dosage (250 mg twice daily) 12, 4],
4
5
6
7
8
9
Acknowledgement The authors arc grateful to K. Schmidt. R. Mueller and K. Fahsel. Bayer AG. Pharma Forschungsanalytik. for HPLC assay.
10
11
References 12 1 Arcicri. G.; Griffith, E.; Gruenwaldt. G.; Heyd. A.; O'Brien. B.; Becker, N.; August. R.: Cipro floxacin: an update on clinical experience. Am. J. Med. 82: suppl. 4A. pp. 381-386 (1987). 2 Bantz. P.-M.; Grotte. J.: Peters-Haertel. W.: Stahmann, J.: Timm. J.: Kasten. R.; Bruck, H.: Low-dose ciprofloxacin in respiratory tract in fections: a randomized comparison with doxycycline in general practice. Am. J. Med. 82: suppl. 4A. pp. 208-210 (1987). 3 Bergan, T.; Dalhoff, A.; Thorsteinsson. S.B.: in
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14
15
2.37
Findcy. R. (ed.): Ciprofloxacin. A new 4-quinolone, pp. 23-36 (Sieber & McIntyre. Hong Kong 1985). Brückner. ().; Trautmann. M.: Efficacy and safe ty in the oral treatment of purulent chest disease and pneumonia with cefixime. ofloxacin, and ci profloxacin. J. Chemother. I: suppl. 4. pp. 782783 (1989). Campbell, D.A.: du Bois. R.M.: Clinical efficacy and safety of ciprofloxacin in the treatment of respiratory tract infections. Proc. 1st Int. Cipro floxacin Workshop. Leverkusen 1986. pp. 245247. Caruso, E.; Galimbcrti. R.: Rohwedder, R.: Dif fusion of ciprofloxacin and metabolites into hu man lung tissue after oral and i.v. dosing (Ab stract 223). Int. Congr. for Infect. Dis.. Rio de Janeiro 1988. Caruso, E.: Castro. J.M.; Chamóles. N.; Galimberti. R.: Jorge, L.; Rohwedder. R.: Penetration of ciprofloxacin into human lung tissue after oral and i.v. dosing. J. Chemother. 1: suppl. 4, pp. 549-551 (1989). Chin. N.-X.: Neu. H.C.: Ciprofloxacin, a quinolonc carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 25: 319-326 (1984). Dalhoff. A.: Ciprofloxacin-Konzentrationen in humanen Geweben nach oraler sowie intrave nöser Applikation. Fortschr. Antimikrob. Anti neoplast. Chemother. 6-3: 479-506 (1987). Easmon. C.S.F.; Crane. J.P.: Uptake of ciproflox acin by human neutrophils. J. Antimicrob. Che mother. 16: 67-73 (1985). Easmon. C.S.F.: Crane. J.P.; Blowers. A.: Effect of ciprofloxacin on intracellular organisms: in vi vo and in vitro studies. J. Antimicrob. Chemo ther. !8: suppl. D. pp. 4.3-48 (1987). Fass. R.J.: In vitro activity of ciprofloxacin (Bay o9867). Antimicrob. Agents Chemother. 24: 568574 (1983). Fass. R.J.: Efficacy and safety of oral ciprofloxa cin in the treatment of serious respiratory infec tions. Am. J. Med. 82: suppl. 4A. pp. 202-207 (1987). Honeybourne. D.; Wise, R.; Andrews. J.M.: Ci profloxacin penetration into lungs. Lancet 1040 (1987). Honeybourne. D.; Andrews. J.M.; Ashby. J.P.; Lodwick, R.; Wise R.: Evaluation of the pene-
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Oral Ciprofloxacin in Lung. Bronchial and Pleural Tissue
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18
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tration of ciprofloxacin and amoxycillin into the bronchial mucosa. Thorax 43: 715-719 (1988). Hoogkamp-Korstanje. J.A.A.: Comparative in vitro activity of five quinolone derivatives and five other antimicrobial agents used in oral ther apy. Eur. J. Clin. M i c r o b i o l . 333-338 (1984). Hoogkamp-Korstanje, J.A.A.; Klein. S.: Efficacy of ciprofloxacin in ambulant patients with respi ratory tract infections. Proc. 1st Int. Ciprofloxa cin Workshop, Leverkusen 1986. pp. 257-259. Reid. T.M.S.; Gould. I.M.; Goldcr. D.; Lcgge, J.S.; Douglas, J.G.; Friend. J.A.R.; Watt. S.J.: Brief report. Respiratory tract penetration of ci profloxacin. Am. J. Med. 87: suppl. 5A, pp. 6061 (1989). Schacht. P.; Deck. K.; Arcieri, G.; Ryoki, T.: Overview of international clinical studies of ci profloxacin, with special reference to safety. Proc. 1st Int. Ciprofloxacin Workshop, Leverku sen 1986. pp. 435-445. Schlenkhoff. D.; Dalhoff, A.; Knopf. J.; Opfcrkuch. W.: Penetration of ciprofloxacin into hu man lung tissue following intravenous injection. Infection 14: 299-300 (1986). Scholl, H.: Schmidt. K.; Weber, B.: Sensitive and selective determination of picogram amounts of ciprofloxacin and its metabolites in biological samples using high-performance liquid chroma tography and photothermal post-column derivatisation. J. Chromatogr. 416: 321-330 (1987). Shrire, L.; Saunders, J.; Traynor, R.; Koornhof, H.J.: A laboratory assessment of ciprofloxacin and comparable antimicrobial agents. Eur. J. Clin. Microbiol. 3: 328-332 (1984).
23 Unertl, K.; Dicterich, H.J.; Ruckdeschel, G.; Martin. E.; Ehrct, W.; Sundcr-Plassmann, L.: Lung tissue and scrum concentrations of cipro floxacin in patients. 15th Int. Congr. Chemother., Istanbul 1987. 24 Volkmann, D.; Brand, P.: Substance character istics of BAY o9867. Pharma-Report 10608(P) (Bayer AG. Pharma Res. Center, Wuppertal). 25 Wise, R.; Andrews, J.M.; Edwards, L.J.: In vitro activity of Bay o9867, a new quinoline derivative, compared with those of other antimicrobial agents. Antimicrob. Agents Chemother. 23: 559564 (1983). 26 Wollschlager, C.M.; Raoof, S.: Khan, F.A.; Guarncri, J.J.; LaBombardi. V.; Afzal, Q.: Controlled, comparative study of ciprofloxacin versus ampicillin in treatment of bacterial respiratory tract infections. Am. J. Med. 82: suppl. 4A, pp. 164— 168 (1987). 27 Zeiler, H.J.; Grohe, K.: The in vitro and in vivo activity of ciprofloxacin. Eur. J. Clin. Microbiol. 3: 339-343 (1984).
Prof. Dr. Tom Bergan Postbox 1108 Blindem N-0317 Oslo 3 (Norway)
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