Research Article: Metronidazole concentration in the bloodstream following its topical application, at different concentration levels, on experimental skin wounds during healing by secondary intention1

Date Published: February 14, 2019

Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em

Author(s): Cláudia Paraguaçu Pupo Sampaio, Maria de Lourdes Pessole Biondo-Simões, Lilian Cristine Teixeira Trindade, Márcia Olandowski, Jorge Eduardo Fouto Matias.


To characterize qualitatively and quantitatively the absorption of
metronidazole solution, in greater concentrations and for longer periods,
when applied topically to an experimental open skin wound model.

An open skin wound, 2 cm in diameter and total skin thickness was prepared,
under anesthetic, in the dorsal region of 108 Wistar rats weighing between
300 and 350 grams. The animals were allocated to groups of 18 animals in
accordance with the concentration of metronidazole in the solution to be
applied daily to the wound. In the control group (CG), 0.9% sodium chloride
solution was used for application, and in the experimental groups (GI, GII,
GIII, GIV and GV) metronidazole solution at 4%, 6%, 8%, 10% and 12%,
respectively, was applied. After 3, 7 and 14 days of treatment. Blood
samples collected through cardiac puncture were examined for the existence
or non-existence of metronidazole, using high performance liquid
chromatography (HPLC). Detected metronidazole values were compared
statistically within each group (temporal analysis 3 days X 7 days X 14
days) and between the groups that used topical metronidazole (4% X 6% X 8% X
10% and 12%) using the Kruskal-Wallis test, considering a statistical
significance of 95% (p<0.05). Metronidazole was detected in all the samples at all times in all the groups in which topical metronidazole was applied to the wounds. Characteristically, there was no significant difference between the doses obtained within each group over time (3 days X 7 days X 14 days) GI=0.461; GII=0.154; GIII=0.888; GIV= 0.264 and GV=0.152. In the evaluation between groups, a similar degree of absorption was found after 3 days (p=0.829) and 14 days (p=0.751). The serum concentration of metronidazole that was achieved was not influenced by the concentration of the solution applied to the skin wound, with similar extend, or by the duration of the application.

Partial Text

Metronidazole (1-beta-hydroxyethyl-2-methyl-5-nitroimidazole) is an active
antibiotic against protozoa (Entamoeba histolytica, Giardia lamblia)1,2 and against obligate anaerobic bacteria, including Bacteroides
fragilis, Clostridium, Fusobacterium, Peptococcus, Peptoestreptococcus,
Eubacterium, Helicobacter, Campilobacter fetus, Espiroquetas and
Gardnerella vaginalis3.

The research project was conducted following the analysis and approval of the Ethics
Committee on the Use of Animals of the Pontifícia Universidade Católica do Paraná.
The project was approved under Protocol Number 654/2012. The study adhered to the
guidelines of Federal Law 11.794 and the recommendations of the Brazilian College of
Animal Experimentation.

The chromatogram that was obtained with the blood sample taken 120 minutes after the
gavage of metronidazole at 4%, in accordance with the calibration method of the
chromatograph, confirmed the sensitivity of the apparatus for the detection of
metronidazole in blood samples. The presence of the same chromatographic peak
confirmed the identity of the substance used in the sample.

As the treatment of wounds and the topical use of active principles improves, with a
wide variety of effects and purposes, it is necessary to gain in-depth knowledge to
discover the possible systemic and local consequences, whether beneficial or not, of
the topical and prolonged application of active substances on different bleeding
areas that cannot be isolated.

The topical application of metronidazole on experimental full-thickness skin, wiht
similar area extent promotes similar absorption, with the detection of low
concentrations in the bloodstream irrespective of the concentration of the solution
applied and the period of time in which it was applied.




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