a The Infectious Diseases Unit, and b Department of Urology, Chaim Sheba Medical Center, Tel Hashomer 52621, Tel Aviv University School of Medicine, Israel
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Abstract |
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Introduction |
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The aim of this study was to investigate whether moxifloxacin, a new fluoroquinolone with anti-Gram-positive and anti-anaerobe activity7,8 might be eliminated through the same sections of the intestine. We used a technique identical to that used in earlier studies, i.e. the measurement of eliminated fluoroquinolone every 15 min during the first 2 h after parenteral administration of the antibiotic. In addition, in the present study we measured the concentration of moxifloxacin in the bile at the same time intervals, because recent reports document substantial secretion via the hepatic route, when the agent was administered intravenously.7,8
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Materials and methods |
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A catheter was inserted into the femoral artery and jugular vein. The first blood sample was withdrawn (time zero) and a freshly prepared solution of moxifloxacin (Bayer AG, Leverkusen, Germany) (15 mg/kg bodyweight) dissolved in phosphate-buffered saline pH 7.3 (Unipath, Denver, CO, USA) was administered via the jugular vein. Blood and bile samples, as well as the fluid samples from each intestinal loop, were withdrawn at 15 min intervals during 120 min. After centrifugation at 2000 rpm for 10 min (Heraeus, Germany, 23 cm rotor) in a cooled centrifuge (+4°C), all samples were frozen until assay.
At the end of the experiment, the animals were killed with sodium barbiturate (pentothal, Abbot SPA, Milan, Italy), and the isolated segments were excised. Each segment was then spread wet and the surface area was measured.
Moxifloxacin concentrations in the fluids examined were measured in duplicate by bioassay with Bacillus subtilis (Bacto Subtilis Spore Suspension, Difco Laboratories, Detroit, MI, USA) on tryptone soya agar pH 9 (Beckton Dickinson Co., Cockeysville, MD, USA). The two major metabolites of moxifloxacin, M1 (N-sulphonate) and M2 (acyl-glucoronide), are pharmacologically inactive8 and thus did not interfere with the bioassay. Standards were prepared using rabbit serum for assay in serum and PBS pH 9.0 for assay in intestinal fluids and bile. Assay plates were incubated at 37°C overnight. The lower limit of sensitivity for the assay was 0.16 mg/L, both in serum and in saline. For statistical analysis the analysis of variance (ANOVA) was used.
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Results |
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Figure 2 demonstrates the relationship between serum AUC and intestinal segment AUCs. Moxifloxacin intestinal elimination rates were 0.019 (± 0.017), 0.011 (± 0.014) and 0.002 (± 0.002) µg/cm2/min, for the three intestinal segments, respectively. Comparison of means by ANOVA yielded the following differences between mean amounts of moxifloxacin eliminated per loop (P < 0.15), and between means of amounts per cm2 for 1 min (P < 0.01) and for 2 h (P < 0.1).
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Discussion |
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Elimination of fluoroquinolone has been demonstrated to occur in the small bowel in rats,3,5,6 in human Caco-2 intestinal cells (representing human small intestinal enterocytes) grown as monolayers4 and in isolated rabbit small intestinal mucosa mounted in Grass chambers.2 For sparfloxacin and ciprofloxacin, elimination through the jejunum, ileum and caecum walls has been demonstrated previously.14 Extra-biliary intestinal secretion of moxifloxacin after iv administration has also been demonstrated in rats.7
Assuming that the length of the jejunum in rabbits is 7085 cm with an average diameter of 1 cm, and the length of the ileum is c. 240 cm with a diameter of 1.3 cm,9 the approximate surface of the jejunum is c. 220270 cm2 and of the ileum is c. 980 cm2. The approximate length of the rabbit caecum is 4045 cm length and the diameter is 34 cm,9 yielding a surface area of c. 380565 cm2. We estimate that 0.6 mg moxifloxacin would be eliminated trans-epithelially through the jejunum, an additional 1.3 mg through the ileum and an additional 0.1 mg through the caecum during the first 2 h following a single iv dose of 15 mg/kg moxifloxacin. Thus, 2 mg or c. 4.5% of the administered dose would be eliminated trans-epithelially in the intestine over the first 2 h following a parenteral administration. It is not known whether this excretory pattern would change in a pharmacokinetic steady state, or if significantly more drug would have been recovered in the intestine if the experiment had lasted longer.
In previous investigations we demonstrated that 2426% of ciprofloxacin and c. 5% of sparfloxacin were eliminated in the small intestine of the rabbit.2,3 Thus, in rabbits, the jejunum and ileum, and to a minor degree the caecum, serve as excretory organs for moxifloxacin with excretory constants close to that of sparfloxacin.5
In the present study a significant amount of moxifloxacin was also excreted via the bile, which may have therapeutic implications for the treatment of biliary infections. The significantly lower excretion of moxifloxacin compared with ciprofloxacin in the intestine may decrease the likelihood of development of resistance in intestinal pathogens such as Salmonella spp., Shigella spp. and enteropathogenic Escherichia coli strains.
Comparison of the patterns of elimination in bile, jejunum, ileum and caecum, with simultaneous blood levels, suggests that the elimination of moxifloxacin in the jejunum and ileum may be a passive diffusion process which is dependent on blood drug concentrations while caecal elimination of moxifloxacin may be an independent (and negligible) process. In contrast, hepatic elimination of moxifloxacin demonstrated a different pattern suggesting an active elimination process.
In summary, moxifloxacin is eliminated in the small bowel and the bile of the rabbit. The net fraction eliminated in the above-mentioned parts of intestine during a 120 min period is in the region of 4.5%.
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Notes |
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References |
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2 . Ramon, J., Dautrey, S., Farinotti, R., Carbon, C. & Rubinstein, E. (1994). Intestinal elimination of ciprofloxacin in rabbits. Antimicrobial Agents and Chemotherapy 38, 75760.[Abstract]
3 . Rubinstein, E., Dautrey, S., Farinotti, R., St Julien, L., Ramonand, J. & Carbon, C. (1995). Intestinal elimination of sparfloxacin, fleroxacin and ciprofloxacin in rats. Antimicrobial Agents and Chemotherapy 39, 99102.[Abstract]
4 . Rubinstein, E., Huneau, J. F., Dumontier, A. M. & Carbon, C. (1992). In vitro and ex vivo intestinal absorption and secretion of sparfloxacin. In Program and Abstracts of the Thirty-Second Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim, CA. Abstract 1463, p. 354. American Society for Microbiology, Washington, DC.
5 . Rubinstein, E., St Julien, L., Ramon, J., Dautrey, S., Farinotti, R., Huneau, J. F. et al. (1994). The intestinal elimination of ciprofloxacin in the rat. Journal of Infectious Diseases 169, 21821.[ISI][Medline]
6 . Vergin, H., Metz, R., Nau, R., Kinzig, M. & Soergel, F. (1993). Elimination of lomefloxacin in rat intestinal loop. Drugs 45, Suppl. 3, 252.
7 . Siefert, H. M., Buhner, K., Domdey-Bette, A., Goller, G., Kohlsdorfer, C. & Steinke, W. (1996). Bay 12-8039, a new 8-methoxyquinolone: Pharmacokinetics in rats and monkeys. In Program and Abstracts of the Thirty-Sixth International Conference on Antimicrobial Agents and Chemotherapy, New Orleans, LA, 1996. Abstract F19, p. 103. American Society for Microbiology, Washington, DC.
8 . Stass, H. & Dalhoff, A. (1997). Determination of Bay 12-9039, a new 8-methoxyquinolone, in human body fluids, by high performance liquid chromatography with fluorescence detection using on-column focusing. Journal of Chromatography. B, Biomedical Sciences and Applications 702, 16374.
9 . Lebas, F., Coudert, P., Rouvier, R. & de Rochambeau, H. (1986). The Rabbit: Husbandry, Health and Production, Animal Production and Health Series, Publication No. 21, pp. 214. Food and Agriculture Organization, Rome.
Received 7 September 1999; returned 16 November 1999; revised 11 January 2000; accepted 21 January 2000