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J Clin Periodontol 2005; 32: 163–166 doi: 10.1111/j.1600-051X.2005.00653.x Metronidazole concentrations in Ene-Renate Pa¨hkla1, Taive Koppel1, 2Pharmacology, University of Tartu, Tartu,Estonia Pa¨hkla E-R, Koppel T, Saag M, Pa¨hkla R: Metronidazole concentrations in plasma,saliva and periodontal pockets in patients with periodontitis. J Clin Peridontol 2005;32:163–166. doi: 10.1111/j.1600–051X.2005.00653.x. r Blackwell Munksgaard,2005.
AbstractObjectives: Metronidazole is widely used antibacterial compound in the treatment ofsome types of periodontal disease. Pharmacokinetics of metronidazole in plasma hasbeen well-described but few data exist about penetration f the drug to the gingivalcrevice fluid. The aim of the present study was to compare the concentrations ofmetronidazole in plasma, saliva and gingival crevice fluid in patients withperiodontitis after multiple administration.
Materials and methods: Eleven patients with severe generalised adult periodontitisparticipated in the study. Metronidazole, 500 mg, was administered orally two or threetimes per day for at least 2 days before sample collection. Samples were collected 2 hafter last dose. Metronidazole concentrations in all fluids were measured with high-performance liquid chromatography.
Results: Mean drug concentrations in palsma, saliva and crevice fluid were 14.33,15.15 and 12.86 mg/ml, respectively. Difference between plasma and crevice fluid orbetween plasma and saliva did not reach statistical significance.
Conclusion: Present study revealed that metronidazole penetrates well into gingivalcrevice fluid and saliva. Metronidazole concentrations in crevice fluid are about equal Key words: gingival fluid; metronidazole; to the protein unbound drug concentrations in plasma. Therefore, general pharmacokinetic data of metronidazole can be also applied in the treatment ofperiodontal disease and in the design of respective treatment regimens.
Berglundh et al. 1998, Winkel et al.
periodontitis (van Winkelhoff et al.
netics of drug at the infection site (Slots et al. 2001, Slots & Ting 2002). Several Table 1. Number of tablets taken by patients per day and individual and mean Æ SD metronidazole concentrations (mg/l) in plasma, saliva and gingival crevice fluid parison, concentrations in adipous tissue and colonic mucosa were significantlylower than respective plasma or serum formed almost two decades ago whenprecise determination methodology was not available. Bioassay measuring thetotal bacteriostatic activity of the sam- flow rate of gingival crevice fluid (Britt dontitis after multiple administration.
were kept frozen overnight at À 201C.
labelled plastic microtube per patient.
ethics committee of University of Tartu.
tion of study protocol and signed written was transferred to the autosampler vial.
tamination of sampling area with saliva.
periodontitis were selected to the study.
perature 22–251C (room temperature).
specificity, limit of detection and quan- fluid samples, for calibration curve con- tification, linearity, precision and accu- variability, stability in the freezer and over concentration range 0.1–50 mg/ml.
Metronidazole pharmacokinetics in periodontitis between plasma and tissue was reached.
ness of fit of linear regression, r2, was flow rate. As antibiotics are used in the (coefficient of variation in the determi- state is a key factor of effectiveness. In dent from the results table, the percent- all patients included to the present study À 3.66 to 0.33% in all concentrations.
(Winkel et al. 1997, Slots & Ting 2002).
tions in samples of different origin with height (Lau et al. 1992, Lamp et al.
microdialysis (Karjagin et al. 2004).
the infection site are of critical impor- events were registered during the study.
study at the same patients but as results crevice fluid obtained per patient ranged into gingival crevice fluid and saliva.
unbound drug concentrations in plasma.
did not reach statistical significance.
good circulation, e.g. muscular tissue.
collection after drug administration.
Estonian Science Foundation No. 5756.
tions in human plasma, saliva, and gingival crevice fluid after single dose. Journal of Lamster, I. B., Vogel, R. I., Hartley, L. J., Position paper: systemic antibiotics in perio- DeGeorge, C. A. & Gordon, J. M. (1985) Lactate dehydrogenase, beta-glucuronidase Goene, R. J., Abbas, F., Winkel, E. G. & de and arylsulfa-tase activity in gingival crevi- Graaff, J. (1989) Metronidazole plus amox- Berglundh, T., Krok, L., Liljenberg, B., West- ycillin in the treatment of Actinobacillus felt, E., Serino, G. & Lindhe, J. (1998) The gingivitis in man. Journal of Periodontology use of metronidazole and amoxicillin in the dontitis. Journal of Clinical Periodontology treatment of advanced periodontal disease. A Lau, A. H., Lam, N. P., Piscitelli, S. C., Wilkes, prospective, controlled trial. Journal of Winkel, E. G., van Winkelhoff, A. J., Timmer- Clinical Periodontology 25, 354–362.
pharmacokinetics of metronidazole and other man, M. F., van der Velden, U. & van der Britt, M. R. & Pohlod, D. J. (1986) Serum and nitroimidazole antiinfectives. Clinical Phar- crevicular fluid concentrations after single metronidazole in the treatment of adultperiodontitis patients. A double-blind place- Loesche, W. J., Giordano, J., Hujoel, P., Schwarcz, J. & Smith, B. A. (1992) Metro- Elter, J. R., Lawrence, H. P., Offenbacher, S. & nidazole in periodontitis: reduced need forsurgery. Journal of Clinical Periodontology Winkel, E. G., van Winkelhoff, A. J., Timmer- Beck, J. D. (1997) Meta-analysis of the effect man, M. F., Vangsted, T. & van der Velden, of systemic metronidazole as an adjunct to Roberts, M. C. (2002) Antibiotic toxicity, scaling and root planing for adult perio- patients with ‘‘refractory’’ periodontitis asso- dontitis. Journal of Periodontal Research 32, ciated with Bacteroides forsythus. Journal of Slots, J. & Ting, M. (2002) Systemic antibiotics Clinical Periodontology 24, 573–579.
Goodson, J. M. (2003) Gingival crevice fluid in the treatment of periodontal disease.
flow. Periodontology 2000 31, 43–54.
Karjagin, J., Pa¨hkla, R. & Starkopf, J. (2004) Perioperative penetration of metronidazole Metronidazole. In: Hardman, J. G., Gilman, into muscle tissue: a microdialysis study.
A. G. & Limbird, L. E. (eds) Goodman and European Journal of Clinical Pharmacology Therapeutics, 9th edition, pp. 995–998.
Lamp, K., Freeman, C. D., Klutman, N. E. & Van Oosten, M. A. C., Notten, F. J. W. & Mikx, pharmacodynamics of nitroimidazole antimi-


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